ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following are discussed in more detail in other sections of the labeling:oHepatic Adverse Drug Reactions [see Warnings and Precautions (5.1)]oInfusion-Related Reactions [see Warnings and Precautions (5.2)]oHypersensitivity Reactions [see Warnings and Precautions (5.3)]oEmbryo-Fetal Toxicity [see Warnings and Precautions (5.4)]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.. oHepatic Adverse Drug Reactions [see Warnings and Precautions (5.1)]. oInfusion-Related Reactions [see Warnings and Precautions (5.2)]. oHypersensitivity Reactions [see Warnings and Precautions (5.3)]. oEmbryo-Fetal Toxicity [see Warnings and Precautions (5.4)]. Most frequent adverse reactions: nausea, vomiting, diarrhea, headache, elevated liver chemistry tests, hypokalemia, constipation, dyspnea, cough, peripheral edema, and back pain. (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. total of 403 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 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 duration of CRESEMBA therapy of greater than 12 weeks, with 52 patients receiving CRESEMBA for over six months.In Trial 1, 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. Treatment-emergent adverse reactions resulting in permanent discontinuation were reported in 37 (14%) CRESEMBA-treated patients and 59 (23%) voriconazole-treated patients. Table includes selected treatment-emergent 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, treatment-emergent 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 and Trial 2.Table 2. Selected Treatment-Emergent Adverse Reactions with Rates of 5% or Greater in CRESEMBA-treated Patients in Trial 1System Organ Class Preferred TermTrial 1CRESEMBA(N=257)n (%)Voriconazole(N=259)n (%)Gastrointestinal disorders Nausea71 (27.6)78 (30.1) Vomiting64 (24.9)73 (28.2) Diarrhea61 (23.7)60 (23.2) Abdominal pain43 (16.7)59 (22.8) Constipation36 (14.0)54 (20.8) Dyspepsia16 (6.2)14 (5.4)General disorders and administration site conditions Edema peripheral39 (15.2)46 (17.8) Fatigue27 (10.5)18 (6.9) Chest pain23 (8.9)16 (6.2) Injection site reaction16 (6.2)4 (1.5)Hepatobiliary disorders Elevated liver laboratory testsElevated 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 Hypokalemia49 (19.1)58 (22.4) Decreased appetite22 (8.6)28 (10.8) Hypomagnesemia14 (5.4)27 (10.4)Musculoskeletal and connective tissue disorders Back pain26 (10.1)19 (7.3)Nervous system disorders Headache43 (16.7)38 (14.7)Psychiatric disorders Insomnia27 (10.5)25 (9.7) DeliriumDelirium includes adverse reactions of agitation, confusional state, delirium, disorientation, and mental status changes. 22 (8.6)30 (11.6) Anxiety21 (8.2)18 (6.9)Renal and urinary disorders Renal failure26 (10.1)21 (8.1)Respiratory, thoracic and mediastinal disorders Dyspnea44 (17.1)35 (13.5) Acute respiratory failure19 (7.4)22 (8.5)Skin and subcutaneous tissue disorders Rash22 (8.6)36 (13.9) Pruritus21 (8.2)15 (5.8)Vascular disorders Hypotension21 (8.2)28 (10.8)The following adverse reactions occurred in less than 5% of all CRESEMBA-treated patients in Trial or 2. The list does not include reactions presented in Table 2. This listing includes adverse reactions where causal relationship to CRESEMBA cannot be ruled out or those which may help the physician in managing the risks to the patients.oBlood and lymphatic system disorders: agranulocytosis, leukopenia, pancytopeniaoCardiac disorders: atrial fibrillation, atrial flutter, bradycardia, reduced QT interval on electrocardiogram, palpitations, supraventricular extrasystoles, supraventricular tachycardia, ventricular extrasystoles, cardiac arrestoEar and labyrinth disorders: tinnitus, vertigooEye disorders: optic neuropathyoGastrointestinal disorders: abdominal distension, gastritis, gingivitis, stomatitisoGeneral disorders and administration site conditions: catheter thrombosis, malaise, chillsoHepatobiliary disorders: cholecystitis, cholelithiasis, hepatitis, hepatomegaly, hepatic failureoImmune system disorders: hypersensitivityoInjury, poisoning and procedural complications: falloMetabolism and nutrition disorders: hypoalbuminemia, hypoglycemia, hyponatremiaoMusculoskeletal and connective tissue disorders: myositis, bone pain, neck painoNervous system disorders: convulsion, dysgeusia, encephalopathy, hypoesthesia, migraine, peripheral neuropathy, paresthesia, somnolence, stupor, syncope, tremoroPsychiatric disorders: confusion, hallucination, depressionoRenal and urinary disorders: hematuria, proteinuriaoRespiratory, thoracic and mediastinal disorders: bronchospasm, tachypneaoSkin and subcutaneous tissue disorders: alopecia, dermatitis, exfoliative dermatitis, erythema, petechiae, urticariaoVascular disorders: thrombophlebitisLaboratory effectsIn 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.. oBlood and lymphatic system disorders: agranulocytosis, leukopenia, pancytopenia. oCardiac disorders: atrial fibrillation, atrial flutter, bradycardia, reduced QT interval on electrocardiogram, palpitations, supraventricular extrasystoles, supraventricular tachycardia, ventricular extrasystoles, cardiac arrest. oEar and labyrinth disorders: tinnitus, vertigo. oEye disorders: optic neuropathy. oGastrointestinal disorders: abdominal distension, gastritis, gingivitis, stomatitis. oGeneral disorders and administration site conditions: catheter thrombosis, malaise, chills. oHepatobiliary disorders: cholecystitis, cholelithiasis, hepatitis, hepatomegaly, hepatic failure. oImmune system disorders: hypersensitivity. oInjury, poisoning and procedural complications: fall. oMetabolism and nutrition disorders: hypoalbuminemia, hypoglycemia, hyponatremia. oMusculoskeletal and connective tissue disorders: myositis, bone pain, neck pain. oNervous system disorders: convulsion, dysgeusia, encephalopathy, hypoesthesia, migraine, peripheral neuropathy, paresthesia, somnolence, stupor, syncope, tremor. oPsychiatric disorders: confusion, hallucination, depression. oRenal and urinary disorders: hematuria, proteinuria. oRespiratory, thoracic and mediastinal disorders: bronchospasm, tachypnea. oSkin and subcutaneous tissue disorders: alopecia, dermatitis, exfoliative dermatitis, erythema, petechiae, urticaria. oVascular disorders: thrombophlebitis. 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 population of uncertain size, it is not always possible to reliably estimate the frequency or establish causal relationship to drug exposure.Immune system disorders: anaphylactic reaction.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. In 2-year rat carcinogenicity study and 2-year mouse carcinogenicity study, dose-related increases in hepatocellular adenomas and/or carcinomas were observed in male and female B6C3F1/Crl mice, and male, but not female Han Wistar rats at doses as low as 0.1 times the exposure seen in humans administered the maintenance dose. Hepatic hemangiomas were increased in female mice at 300 mg/kg, at an exposure similar to the maintenance dose. Hepatoblastoma were increased in male mice at 100 mg/kg, about 0.4 times the systemic exposures based on AUC comparisons. Thyroid follicular cell adenomas were observed in male and female rats at doses as low as 60 mg/kg in male rats (about 0.2 times the human clinical maintenance dose). The relevance of the rat thyroid tumors to human carcinogenic risk remains unclear.A significant increase in the incidence of skin fibromas was seen in male rats at 300 mg/kg, exposures 0.8 times the human exposure at the human clinical maintenance dose. Uterine adenocarcinomas were observed in female rats at 200 mg/kg, at systemic exposures similar to the human exposure at the human clinical maintenance dose.No mutagenic or clastogenic effects were detected in the in vitro bacterial reverse mutation assay and the in vivo bone marrow micronucleus assay in rats.Oral administration of isavuconazonium sulfate did not affect the fertility in male or female rats treated at doses up to 90 mg/kg/day (approximately 0.3 times the systemic exposure at the human clinical maintenance dose).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Isavuconazonium sulfate is the prodrug of isavuconazole, an azole antifungal [see Microbiology (12.4)].. 12.2 Pharmacodynamics. Pharmacokinetic/Pharmacodynamic Relationship. In patients treated with CRESEMBA for invasive aspergillosis in controlled trial, there was no significant association between plasma AUC or plasma isavuconazole concentration and efficacy.. Cardiac Electrophysiology. The effect on QTc interval of multiple doses of CRESEMBA capsules was evaluated. CRESEMBA was administered as capsules (equivalent to 200 mg isavuconazole) three times daily on days and followed by either capsules or capsules (equivalent to 600 mg isavuconazole) once daily for 13 days in randomized, placebo- and active-controlled (moxifloxacin 400 mg single-dose), four-treatment-arm, parallel study in 160 healthy subjects.Isavuconazole resulted in dose-related shortening of the QTc interval. For the 2-capsule dosing regimen, the least squares mean (LSM) difference from placebo was -13.1 msec at hours postdose [90% CI: -17.1, -9.1 msec]. Increasing the dose to capsules resulted in an LSM difference from placebo of -24.6 msec at hours postdose [90% CI: -28.7, -20.4]. CRESEMBA was not evaluated in combination with other drugs that reduce the QTc interval, so the additive effects are not known.. 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 5). Based on population pharmacokinetics analysis of healthy subjects and patients, the mean plasma half-life of isavuconazole was 130 hours and the mean volume of distribution (Vss) was approximately 450 following intravenous administration.Table 5. Steady State Pharmacokinetic Parameters of Isavuconazole Following Administration of CRESEMBA CapsulesParameterCRESEMBA CapsulesEach capsule contains the equivalent of 100 mg of isavuconazole.(n 37)CRESEMBA Capsules(n 32)Cmax (ng/mL)MeanSDCV %74991893.325.2200283584.317.9tmax (h)MedianRange3.0002.0 4.04.0002.0 4.0AUC (hong/mL)MeanSDCV %12140235768.829.535280572018.520.4. Absorption. After oral administration of CRESEMBA in healthy volunteers, the active moiety, isavuconazole, generally reaches maximum plasma concentrations (Cmax) hours to 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 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 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 6).Table 6. Statistical Comparison of Plasma Pharmacokinetics of Isavuconazole Following Single Oral Dose Administration of 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 Subjects Under Fasted Conditions CRESEMBA IV Solution via NG TubeCRESEMBA Oral CapsulesNG Tube/Oral CapsulePharmacokinetic ParameterNMean (%CV)NMean (%CV)GMR (90% CI)Cmax (ng/mL)132295 (23.6)132185 (26.7)105.34 (89-124)AUC0-72hr (hr.ng/mL)1334885 (22.1)1335777 (24.6)97.81 (93-103)AUC0- (hr.ng/mL)1298142 (44.5)12100050 (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 high-fat meal reduced isavuconazole Cmax by 9% and increased AUC by 9%. CRESEMBA can be taken with or without food. Distribution. Isavuconazole is extensively distributed with mean steady state volume of distribution (Vss) of approximately 450 L. Isavuconazole is highly protein bound (greater than 99%), predominantly to albumin.. Metabolism. In in vitro studies isavuconazonium sulfate is rapidly hydrolyzed in blood to isavuconazole by esterases, predominantly by butylcholinesterase. Isavuconazole is substrate of cytochrome P450 enzymes 3A4 and 3A5.Following single doses of [cyano 14C] isavuconazonium and [pyridinylmethyl 14C] isavuconazonium in humans, in addition to the active moiety (isavuconazole) and the inactive cleavage product, 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, 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 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 CRESEMBA in pediatric patients have not been evaluated.. Race. 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 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 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 difference in AUC for elderly females, see Geriatric section above. No dose adjustment is required based on gender.. Renal Impairment. Total isavuconazole AUC and Cmax were not affected to 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. dose adjustment is not warranted in patients with ESRD.. Hepatic Impairment. After 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 group and the Child-Pugh Class group, respectively, relative to 32 age and weight-matched healthy subjects with normal hepatic function. Mean Cmax was 2% lower in the Child-Pugh Class group and 30% lower in the Child-Pugh Class 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 StudiesIsavuconazole is substrate of CYP3A4 and CYP3A5. In vitro, isavuconazole is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Isavuconazole is also an inhibitor of P-gp-, BCRP- and OCT2-mediated drug transporters. In vitro, isavuconazole is also an inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9.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 strong CYP3A4 inhibitor, ketoconazole increased the isavuconazole Cmax by 9% and isavuconazole AUC by 422% after multiple-dose administration of ketoconazole (200 mg twice daily) for 24 days and single-dose of CRESEMBA equivalent to 200 mg of isavuconazole. Isavuconazole is sensitive CYP3A4 substrate and use with strong CYP3A4 inhibitors are contraindicated per Section and Figure 1.Lopinavir/Ritonavir: Lopinavir/ritonavir (400 mg/100 mg twice daily) increased the Cmax 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 Cmax 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 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 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 12.4 Microbiology. Mechanism of ActionIsavuconazonium sulfate is the prodrug of isavuconazole, an azole antifungal drug. Isavuconazole inhibits the synthesis of ergosterol, key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14-alpha-demethylase. This enzyme is responsible for the conversion of lanosterol to ergosterol. An accumulation of methylated sterol precursors and depletion of ergosterol within the fungal cell membrane weakens the membrane structure and function. Mammalian cell demethylation is less sensitive to isavuconazole inhibition.ResistanceThere is potential for development of resistance to isavuconazole.The mechanism of resistance to isavuconazole, like other azole antifungals, is likely due to multiple mechanisms that include substitutions in the target gene CYP51. Changes in sterol profile and elevated efflux pump activity were observed; however, the clinical relevance of these findings is unclear.In vitro and animal studies suggest cross-resistance between isavuconazole and other azoles. The relevance of cross-resistance to clinical outcome has not been fully characterized; however, patients failing prior azole therapy may require alternative antifungal therapy.Antimicrobial ActivityIsavuconazole has activity against most strains of the following microorganisms, both in vitro and in clinical infections: Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, and Mucorales such as Rhizopus oryzae and Mucormycetes species [see Clinical Studies (14)].Susceptibility TestingFor specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Treatment of Invasive Aspergillosis. Trial was randomized, double-blind, non-inferiority active controlled trial which evaluated the safety and efficacy of CRESEMBA versus voriconazole for primary treatment of invasive fungal disease caused by Aspergillus species or other filamentous fungi. Eligible patients had proven, probable, or possible invasive fungal infections per European Organisation for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria1. Patients were stratified by history of allogeneic bone marrow transplant, uncontrolled malignancy at baseline, and by geographic region. The mean age of patients was 51 years (range 17-87) and the majority were Caucasians (78%), male (60%), with fungal disease involving the lungs (95%). At least one Aspergillus species was identified in 30% of the subjects; A. fumigatus and A. flavus were the most common pathogens identified. There were few patients with other Aspergillus species: A. niger, A. sydowii, A. terreus, and A. westerdijkiae. Baseline risk factors are presented in Table 7.Table 7. Baseline Risk Factors in Intent-To-Treat (ITTITT includes all randomized patients who received at least one dose of study drug.) PopulationCRESEMBAN=258n (%)VoriconazoleN=258n (%)Hematologic Malignancy211 (82)222 (86)Allogeneic Hematopoietic Stem Cell Transplant54 (21)51 (20)NeutropeniaNeutropenia defined as less than 500 cells/mm3.163 (63)175 (68)Corticosteroid Use48 (19)39 (15)T-Cell Immunosuppressant Use111 (43)109 (42)Patients randomized to receive CRESEMBA treatment were administered loading dose intravenously of 372 mg of isavuconazonium sulfate (equivalent to 200 mg of isavuconazole) every hours for the first 48 hours. Beginning on Day 3, patients received intravenous or oral therapy of 372 mg of isavuconazonium sulfate (equivalent to 200 mg of isavuconazole) once daily. Patients randomized to receive voriconazole treatment were administered voriconazole intravenously with loading dose of mg/kg every 12 hours for the first 24 hours followed by mg/kg intravenously every 12 hours for the following 24 hours. Therapy could then be switched to an oral formulation of voriconazole at dose of 200 mg every 12 hours. In this trial, the protocol-defined maximum treatment duration was 84 days. Mean treatment duration was 47 days for both treatment groups, of which to days was by an intravenous route of administration.All-cause mortality through Day 42 in the overall population (ITT) was 18.6% in the CRESEMBA treatment group and 20.2% in the voriconazole treatment group for an adjusted treatment difference of -1.0% with 95% confidence interval of -8.0% to 5.9%. Similar results were seen in patients with proven or probable invasive aspergillosis confirmed by serology, culture or histology (see Table 8).Table 8. All-Cause Mortality Through Day 42CRESEMBAVoriconazoleNAll-cause Mortalityn (%)NAll-cause Mortalityn (%)DifferenceAdjusted treatment difference (CRESEMBA-voriconazole) by Cochran-Mantel-Haenszel method stratified by the randomization factors.(95% CI)%ITT25848 (18.6)25852 (20.2)-1.0 (-8.0, 5.9)Proven or ProbableInvasive Aspergillosis12323 (18.7)10824 (22.2)-2.7 (-13.6, 8.2)Overall success at End-of-Treatment (EOT) was assessed by blinded, independent Data Review Committee (DRC) using pre-specified clinical, mycological, and radiological criteria. In the subgroup of patients with proven or probable invasive aspergillosis confirmed by serology, culture or histology, overall success at EOT was seen in 35% of CRESEMBA-treated patients compared to 38.9% of voriconazole-treated patients (see Table 9).Table 9. Overall Response Success at End-of-TreatmentCRESEMBAVoriconazoleNSuccessn (%)NSuccessn (%)DifferenceAdjusted treatment difference (CRESEMBA-voriconazole) by Cochran-Mantel-Haenszel method stratified by the randomization factors.(95% CI)%Proven or ProbableInvasive Aspergillosis12343 (35.0)10842 (38.9)-4.0 (-16.3, 8.4). 14.2 Treatment of Invasive Mucormycosis. Trial 2, an open-label, non-comparative trial, evaluated the safety and efficacy of subset of patients with invasive mucormycosis. Thirty-seven (37) patients had proven or probable mucormycosis according to criteria based on those established by the European Organisation for Research and Treatment of Cancer/Mycoses Study Group1. Rhizopus oryzae and Mucormycetes were the most common pathogens identified. There were few patients with other Mucorales: Lichtheimia corymbifera, Mucor amphibiorum, Mucor circinelloides, Rhizomucor pusillus, Rhizopus azygosporus, and Rhizopus microsporus. The patients were white (68%), male (81%), and had mean age of 49 years (range 22-79). Fifty-nine percent (59%) of patients had pulmonary disease involvement, half of whom also had other organ involvement. The most common non-pulmonary disease locations were sinus (43%), eye (19%), CNS (16%) and bone (14%). Baseline risk factors are presented in Table 10. The Independent Data Review Committee classified patients receiving CRESEMBA as primary therapy, or for invasive mold disease refractory to, or patients intolerant of other antifungal therapy.Table 10. Baseline Risk Factors in Mucorales PatientsTherapy status assessed by the Independent Data Review Committee: Primary patients received CRESEMBA as primary treatment; refractory patients underlying infection not adequately treated by prior therapy; intolerant patients unable to tolerate prior therapy. PrimaryN=21n (%)RefractoryN=11n (%)IntolerantN=5n (%)Total N=37n (%)Hematologic Malignancy11 (52)7 (64)4 (80)22 (60)Allogeneic Hematopoietic Stem Cell Transplant4 (19)4 (36)5 (100)13 (35)NeutropeniaNeutropenia is defined as less than 500 cells/mm3.4 (19)5 (46)1 (20)10 (27)Corticosteroid Use5 (24)3 (27)2 (40)10 (27)T-Cell Immunosuppressant Use7 (33)6 (55)5 (100)18 (49)Diabetic4 (19)004 (11)Patients were treated with CRESEMBA intravenously or via oral administration at the recommended doses. Median treatment duration was 102 days for patients classified as primary, 33 days for refractory, and 85 days for intolerant [see Dosage and Administration (2.2)].For patients with invasive mucormycosis, all-cause mortality through Day 42 and success in overall response at the End-of-Treatment as assessed by the Independent Data Review Committee is shown in Table 11. These results provide evidence that CRESEMBA is effective for the treatment of mucormycosis, in light of the natural history of untreated mucormycosis. However, the efficacy of CRESEMBA for the treatment of invasive mucormycosis has not been evaluated in concurrent, controlled clinical trials.Table 11. All-Cause Mortality and Overall Response Success in Mucorales PatientsPrimaryN=21RefractoryN=11IntolerantN=5TotalN=37All-cause MortalityThrough Day 427 (33%)5 (46%)2 (40%)14 (38%)Overall ResponseSuccess Rate atEnd-of-Treatment6/19Two primary mucormycosis patients were not assessed at End-of-Treatment due to ongoing treatment. (32%)4/11 (36%)1/5 (20%)11/35 (31%).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. oCRESEMBA is contraindicated in persons with known hypersensitivity to isavuconazole.oCoadministration of strong CYP3A4 inhibitors, such as ketoconazole or high-dose ritonavir (400 mg every 12 hours), with CRESEMBA is contraindicated because strong CYP3A4 inhibitors can significantly increase the plasma concentration of isavuconazole [see Drug Interactions (7) and Clinical Pharmacology (12.3)].oCoadministration of strong CYP3A4 inducers, such as rifampin, carbamazepine, St. Johns wort, or long acting barbiturates with CRESEMBA is contraindicated because strong CYP3A4 inducers can significantly decrease the plasma concentration of isavuconazole [see Drug Interactions (7) and Clinical Pharmacology (12.3)].oCRESEMBA shortened the QTc interval in concentration-related manner. CRESEMBA is contraindicated in patients with familial short QT syndrome [see Clinical Pharmacology (12.2)]. oCRESEMBA is contraindicated in persons with known hypersensitivity to isavuconazole.. oCoadministration of strong CYP3A4 inhibitors, such as ketoconazole or high-dose ritonavir (400 mg every 12 hours), with CRESEMBA is contraindicated because strong CYP3A4 inhibitors can significantly increase the plasma concentration of isavuconazole [see Drug Interactions (7) and Clinical Pharmacology (12.3)].. oCoadministration of strong CYP3A4 inducers, such as rifampin, carbamazepine, St. Johns wort, or long acting barbiturates with CRESEMBA is contraindicated because strong CYP3A4 inducers can significantly decrease the plasma concentration of isavuconazole [see Drug Interactions (7) and Clinical Pharmacology (12.3)].. oCRESEMBA shortened the QTc interval in concentration-related manner. CRESEMBA is contraindicated in patients with familial short QT syndrome [see Clinical Pharmacology (12.2)]. oHypersensitivity to CRESEMBA. (4)oCoadministration with strong CYP3A4 inhibitors, such as ketoconazole or high-dose ritonavir. (4, 7)oCoadministration with strong CYP3A4 inducers, such as rifampin, carbamazepine, St. Johns wort, or long acting barbiturates. (4, 7)oUse in patients with familial short QT syndrome. (4). oHypersensitivity to CRESEMBA. (4). oCoadministration with strong CYP3A4 inhibitors, such as ketoconazole or high-dose ritonavir. (4, 7). oCoadministration with strong CYP3A4 inducers, such as rifampin, carbamazepine, St. Johns wort, or long acting barbiturates. (4, 7). oUse in patients with familial short QT syndrome. (4).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. CRESEMBA(R) is an azole antifungal indicated for use in the treatment of: oInvasive aspergillosis. (1.1)oInvasive mucormycosis. (1.2). oInvasive aspergillosis. (1.1). oInvasive mucormycosis. (1.2). 1.1 Invasive Aspergillosis. CRESEMBA(R) is an azole antifungal indicated for patients 18 years of age and older for the treatment of invasive aspergillosis [see Clinical Studies (14.1) and Clinical Pharmacology (12.4)].. 1.2 Invasive Mucormycosis. CRESEMBA is an azole antifungal indicated for patients 18 years of age and older for the treatment of invasive mucormycosis [see Clinical Studies (14.2) and Clinical Pharmacology (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.

DESCRIPTION SECTION.

11 DESCRIPTION. 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-[(2R,3R)-3-[4-(4-cyanophenyl)-2-thiazolyl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-4H-1,2,4-triazolium-4-yl]ethoxy]carbonyl]methylamino]-3-pyridinyl]methyl ester, sulfate (1:1). The empirical formula is C35H35F2N8O5S.HSO4, the molecular weight is 814.84 and the structural formula is:CRESEMBA (isavuconazonium sulfate) capsules are available for oral administration. Each CRESEMBA capsule contains 186 mg isavuconazonium sulfate, equivalent to 100 mg isavuconazole. The inactive ingredients include magnesium citrate, microcrystalline cellulose, talc, colloidal silicon dioxide, stearic acid, hypromellose, red iron oxide, titanium dioxide, purified water, gellan gum, potassium acetate, disodium edetate, sodium laurylsulfate, shellac, propylene glycol, strong ammonia solution, potassium hydroxide and black iron oxide.CRESEMBA (isavuconazonium sulfate) for injection is available for intravenous administration. CRESEMBA for injection is 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.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oCRESEMBA for injection must be administered through an in-line filter over minimum of hour. (2.1, 2.4)oLoading Dose: 372 mg isavuconazonium sulfate (equivalent to 200 mg of isavuconazole) every hours for doses (48 hours) via oral (2 capsules) or intravenous administration (1 reconstituted vial). (2.2)oMaintenance Dose: 372 mg isavuconazonium sulfate (equivalent to 200 mg of isavuconazole) once daily via oral (2 capsules) or intravenous administration (1 reconstituted vial) starting 12 to 24 hours after the last loading dose. (2.2)oCapsules can be taken with or without food. (2.2). oCRESEMBA for injection must be administered through an in-line filter over minimum of hour. (2.1, 2.4). oLoading Dose: 372 mg isavuconazonium sulfate (equivalent to 200 mg of isavuconazole) every hours for doses (48 hours) via oral (2 capsules) or intravenous administration (1 reconstituted vial). (2.2). oMaintenance Dose: 372 mg isavuconazonium sulfate (equivalent to 200 mg of isavuconazole) once daily via oral (2 capsules) or intravenous administration (1 reconstituted vial) starting 12 to 24 hours after the last loading dose. (2.2). oCapsules can be taken with or without food. (2.2). 2.1 Important Instructions for Intravenous Administration. oIntravenous formulation must be administered via an infusion set with an in-line filter (pore size 0.2 to 1.2 micron).oInfuse the intravenous formulation over minimum of hour in 250 mL of compatible diluent, to reduce the risk for infusion-related reactions. Do not administer as an intravenous bolus injection.oDo not infuse CRESEMBA with other intravenous medications.oFlush intravenous lines with 0.9% sodium chloride injection, USP or 5% dextrose injection, USP prior to and after infusion of CRESEMBA.oAfter dilution of the intravenous formulation, avoid unnecessary vibration or vigorous shaking of the solution. Do not use pneumatic transport system.. oIntravenous formulation must be administered via an infusion set with an in-line filter (pore size 0.2 to 1.2 micron).. oInfuse the intravenous formulation over minimum of hour in 250 mL of compatible diluent, to reduce the risk for infusion-related reactions. Do not administer as an intravenous bolus injection.. oDo not infuse CRESEMBA with other intravenous medications.. oFlush intravenous lines with 0.9% sodium chloride injection, USP or 5% dextrose injection, USP prior to and after infusion of CRESEMBA.. oAfter dilution of the intravenous formulation, avoid unnecessary vibration or vigorous shaking of the solution. Do not use pneumatic transport system.. 2.2 Dosage Regimen. CRESEMBA (isavuconazonium sulfate) is the prodrug of isavuconazole, an azole antifungal drug. Prescribe CRESEMBA as shown in Table below.Table 1. Dosage Regimen for CRESEMBALoading DoseMaintenance DoseStart maintenance doses 12 to 24 hours after the last loading doseCRESEMBA for Injection372 mg372 mg of isavuconazonium sulfate is equivalent to 200 mg of isavuconazole of isavuconazonium sulfate per vial1 reconstituted vial (372 mg)intravenouslyevery hours for doses (48 hours)1 reconstituted vial (372 mg)intravenouslyonce dailyCRESEMBA Capsules186 mg186 mg of isavuconazonium sulfate is equivalent to 100 mg of isavuconazole of isavuconazonium sulfate per capsule2 capsules (372 mg)orallyevery hours for doses (48 hours)2 capsules (372 mg)orallyonce dailySwitching 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 capsules whole. Do not chew, crush, dissolve, or open the capsules. CRESEMBA capsules can be taken with or without food.. 2.3 Reconstitution Instructions for the 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.oReconstitute one vial of CRESEMBA by adding mL water for injection, USP to the vial.oGently shake to dissolve the powder completely.oVisually inspect the reconstituted solution for particulate matter and discoloration. Reconstituted CRESEMBA should be clear and free of visible particulate.oThe reconstituted solution may be stored below 25C for maximum of hour prior to preparation of the patient intravenous infusion solution [see Dosage and Administration (2.4)]. oFor nasogastric tube administration, the reconstituted solution should be administered within hour of reconstitution [see Dosage and Administration (2.5)].. oReconstitute one vial of CRESEMBA by adding mL water for injection, USP to the vial.. oGently shake to dissolve the powder completely.. oVisually inspect the reconstituted solution for particulate matter and discoloration. Reconstituted CRESEMBA should be clear and free of visible particulate.. oThe reconstituted solution may be stored below 25C for maximum of hour prior to preparation of the patient intravenous infusion solution [see Dosage and Administration (2.4)]. oFor nasogastric tube administration, the reconstituted solution should be administered within hour of reconstitution [see Dosage and Administration (2.5)].. 2.4 Dilution and Preparation Instructions for the Intravenous Administration of the Injection Formulation. oRemove mL of the reconstituted solution from the vial and add it to an infusion bag containing 250 mL (approximately 1.5 mg isavuconazonium sulfate per mL) of compatible diluent. The diluted solution may show visible translucent to white particulates of isavuconazole (which will be removed by in-line filtration).oUse gentle mixing or roll bag to minimize the formation of particulates. Avoid unnecessary vibration or vigorous shaking of the solution.oApply in-line filter with microporous membrane pore size of 0.2 to 1.2 micron and in-line filter reminder sticker to the infusion bag.oDo not use pneumatic transport system.oThe intravenous administration should be completed within hours of dilution at room temperature. If this is not possible, immediately refrigerate (2C to 8C 36F to 46F) the infusion solution after dilution and complete the infusion within 24 hours. Do not freeze the infusion solution.. oRemove mL of the reconstituted solution from the vial and add it to an infusion bag containing 250 mL (approximately 1.5 mg isavuconazonium sulfate per mL) of compatible diluent. The diluted solution may show visible translucent to white particulates of isavuconazole (which will be removed by in-line filtration).. oUse gentle mixing or roll bag to minimize the formation of particulates. Avoid unnecessary vibration or vigorous shaking of the solution.. oApply in-line filter with microporous membrane pore size of 0.2 to 1.2 micron and in-line filter reminder sticker to the infusion bag.. oDo not use pneumatic transport system.. oThe intravenous administration should be completed within hours of dilution at room temperature. If this is not possible, immediately refrigerate (2C to 8C 36F to 46F) the infusion solution after dilution and complete the infusion within 24 hours. Do not freeze the infusion solution.. 2.5 Preparation Instructions for the Nasogastric Tube Administration of the Injection Formulation. oUtilizing aseptic technique, reconstitute one vial of CRESEMBA for injection (equivalent to 200 mg isavuconazole) with mL of water for injection, USP [see Dosage and Administration (2.3)]. oWithdraw the entire contents (5 mL) of the vial using an appropriate syringe and needle. Discard the needle and cap the syringe. oTo 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 mL rinses to the NG tube with water [see Clinical Pharmacology (12.3)]. oThe reconstituted solution should be administered via nasogastric tube within hour of reconstitution.. oUtilizing aseptic technique, reconstitute one vial of CRESEMBA for injection (equivalent to 200 mg isavuconazole) with mL of water for injection, USP [see Dosage and Administration (2.3)]. oWithdraw the entire contents (5 mL) of the vial using an appropriate syringe and needle. Discard the needle and cap the syringe. oTo 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 mL rinses to the NG tube with water [see Clinical Pharmacology (12.3)]. oThe reconstituted solution should be administered via nasogastric tube within hour of reconstitution.. 2.6 Compatibility for the Injection Formulation CRESEMBA for injection should only be administered with the following diluents:o0.9% sodium chloride injection, USPo5% dextrose injection, USP. o0.9% sodium chloride injection, USP. o5% dextrose injection, USP.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Each CRESEMBA capsule contains 186 mg isavuconazonium sulfate (equivalent to 100 mg of isavuconazole). Capsules are opaque and elongated and have Swedish orange (reddish-brown) body imprinted with the Astellas logo in black ink and white cap imprinted with 766 in black ink.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 single-dose vial as sterile lyophilized white to yellow powder.. oCRESEMBA capsules contain 186 mg of isavuconazonium sulfate (equivalent to 100 mg of isavuconazole). (3)oCRESEMBA for injection is supplied in single-dose vial as sterile lyophilized powder containing 372 mg of isavuconazonium sulfate (equivalent to 200 mg of isavuconazole). (3). oCRESEMBA capsules contain 186 mg of isavuconazonium sulfate (equivalent to 100 mg of isavuconazole). (3). oCRESEMBA for injection is supplied in single-dose vial as sterile lyophilized powder containing 372 mg of isavuconazonium sulfate (equivalent to 200 mg of isavuconazole). (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Isavuconazole is sensitive substrate of CYP3A4. CYP3A4 inhibitors or inducers may alter the plasma concentrations of isavuconazole.Isavuconazole is moderate inhibitor of CYP3A4, and mild inhibitor of P-glycoprotein (P-gp), and organic cation transporter (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 [see Clinical Pharmacology (12.3)].Table 3. Drug(s) Affecting Pharmacokinetics of CRESEMBARecommendationCommentsKetoconazoleContraindicate coadministration of all potent CYP3A4 inhibitorsThere is more than 5-fold increase in exposure of isavuconazole upon coadministration with ketoconazole [see Clinical Pharmacology (12.3)].Lopinavir/ritonavir400 mg of lopinavir in combination with 100 mg of ritonavir. Caution is advised when CRESEMBA is coadministered with lopinavir/ritonavirThere is 96% increase in exposure of isavuconazole when coadministered with lopinavir/ritonavir [see Clinical Pharmacology (12.3)].RifampinContraindicate coadministration of all potent CYP3A4 inducersThere is 97% decrease in exposure of isavuconazole upon coadministration with rifampin [see Clinical Pharmacology (12.3)].Table 4. The Effect of CRESEMBA on the Pharmacokinetics of Other DrugsRecommendationCommentsLopinavir/ritonavir400 mg of lopinavir in combination with 100 mg of ritonavir. Use with CautionConcomitant administration of lopinavir/ritonavir and CRESEMBA resulted in decreased exposure of lopinavir and ritonavir that could possibly result in loss of antiviral efficacy [see Clinical Pharmacology (12.3)].AtorvastatinUse with Caution Caution should be used when atorvastatin is used with CRESEMBA due to potential increase in atorvastatin exposure. Monitor patients for adverse reactions that are typical of atorvastatin [see Clinical Pharmacology (12.3)].CyclosporineUse with CautionConcomitant administration of CRESEMBA and cyclosporine results in increase in cyclosporine exposure. Monitor drug concentrations of cyclosporine and adjust dose as needed [see Clinical Pharmacology (12.3)].SirolimusUse with CautionConcomitant administration of CRESEMBA and sirolimus results in increase in sirolimus exposure. Monitor drug concentrations of sirolimus and adjust dose as needed [see Clinical Pharmacology (12.3)].TacrolimusUse with CautionConcomitant administration of CRESEMBA and tacrolimus results in increase in tacrolimus exposure. Monitor drug concentrations of tacrolimus and adjust dose as needed [see Clinical Pharmacology (12.3)].MidazolamUse with CautionConcomitant administration of CRESEMBA and midazolam results in increase in midazolam exposure. Consider dose reduction of midazolam when isavuconazole is coadministered [see Clinical Pharmacology (12.3)].BupropionUse with CautionConcomitant 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 [see Clinical Pharmacology (12.3)].Mycophenolate MofetilUse with CautionConcomitant administration of CRESEMBA and MMF results in increase in MMF exposure. Patients receiving CRESEMBA concurrently with MMF should be monitored for MPA-related toxicities [see Clinical Pharmacology (12.3)].DigoxinUse with CautionConcomitant 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 [see Clinical Pharmacology (12.3)].. oCYP3A4 inhibitors or inducers may alter the plasma concentrations of isavuconazole. (7)oAppropriate therapeutic drug monitoring and dose adjustment of immunosuppressants (i.e., tacrolimus, sirolimus, and cyclosporine) may be necessary when coadministered with CRESEMBA. (7)oDrugs with narrow therapeutic window that are P-gp substrates, such as digoxin, may require dose adjustment when administered concomitantly with CRESEMBA. (7). oCYP3A4 inhibitors or inducers may alter the plasma concentrations of isavuconazole. (7). oAppropriate therapeutic drug monitoring and dose adjustment of immunosuppressants (i.e., tacrolimus, sirolimus, and cyclosporine) may be necessary when coadministered with CRESEMBA. (7). oDrugs with narrow therapeutic window that are P-gp substrates, such as digoxin, may require dose adjustment when administered concomitantly with CRESEMBA. (7).

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential ContraceptionCRESEMBA may cause embryo-fetal harm when administered to pregnant women [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1)]. Advise female patients of reproductive potential to use effective contraception during treatment with CRESEMBA and for 28 days after the final dose.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the 547 patients who received CRESEMBA in the Phase and trials, 86 (16%) of patients were greater than 65 years of age and 20 (4%) were greater than 75 years of age. The pharmacokinetics of isavuconazole are comparable in young and elderly subjects (65 years of age and older) [see Clinical Pharmacology (12.3)]. No dose adjustment of CRESEMBA is needed in elderly patients.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. CapsulesCRESEMBA (isavuconazonium sulfate) capsules are available in aluminum blister packs. Each capsule contains 186 mg isavuconazonium sulfate (equivalent to 100 mg of isavuconazole). Capsules are opaque and elongated and have Swedish orange (reddish-brown) body imprinted with the Astellas logo in black ink and white cap imprinted with 766 in black ink. Store in original container to protect from moisture. Capsules are packaged in aluminum blister packs, seven (7) capsules per sheet with desiccant. (NDC 0469-0520-14) Injection CRESEMBA (isavuconazonium sulfate) for injection is supplied in single-dose vial as white to yellow sterile lyophilized powder containing 372 mg isavuconazonium sulfate (equivalent to 200 mg isavuconazole). Individually packaged vials are available for intravenous administration. (NDC 0469-0420-99). 16.2 Storage and Handling. Store CRESEMBA capsules at 20C to 25C (68F to 77F) in the original packaging to protect from moisture. Excursions are permitted from 15C to 30C (59F to 86F) [See USP Controlled Room Temperature].Store CRESEMBA for injection unreconstituted vials at 2C to 8C (36F to 46F) in refrigerator. CRESEMBA is single-dose vial of unpreserved sterile lyophile. Following reconstitution of the lyophile with water for injection USP, the reconstituted solution should be used immediately, or stored below 25C for maximum of hour prior to preparation of the patient infusion solution. The prepared infusion solution should be kept for not more than hours at room temperature [20C to 25C (68F to 77F)] or 24 hours at 2C to 8C (36F to 46F) prior to use. CRESEMBA for injection vials are for single-dose use only.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).Advise patients that CRESEMBA can be taken with or without food. Each capsule should be swallowed whole. Do not chew, crush, dissolve, or open the capsules.Advise patients to inform their physician if they are taking other drugs or before they begin taking other drugs as certain drugs can decrease or increase the plasma concentrations of CRESEMBA.CRESEMBA can decrease or increase the plasma concentrations of other drugs. Advise patients to inform their physician if they are pregnant, plan to become pregnant, or are nursing.Advise patients to inform their physician immediately if they have ever had an allergic reaction to isavuconazole or other antifungal medicines such as ketoconazole, fluconazole, itraconazole, posaconazole, or voriconazole. Advise patients to discontinue CRESEMBA and seek immediate medical attention if any signs or symptoms of severe allergic reaction occur [see Warnings and Precautions (5.3)]. Marketed and Distributed by: Astellas Pharma US, Inc. Northbrook, IL 60062 CRESEMBA is registered trademark of Astellas US LLC.Licensed from: Basilea Pharmaceutica International Ltd. 312370-ISA-USA.

LACTATION SECTION.

8.2 Lactation Risk SummaryThere are no data on the presence of isavuconazole in human milk, the effects on the breastfed infant or the effects on milk production. Isavuconazole was present in the milk of lactating rats following intravenous administration. When drug is present in animal milk, it is likely that the drug will be present in human milk. Therefore, breastfeeding should be discontinued during treatment with CRESEMBA.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Isavuconazonium sulfate is the prodrug of isavuconazole, an azole antifungal [see Microbiology (12.4)].

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. In 2-year rat carcinogenicity study and 2-year mouse carcinogenicity study, dose-related increases in hepatocellular adenomas and/or carcinomas were observed in male and female B6C3F1/Crl mice, and male, but not female Han Wistar rats at doses as low as 0.1 times the exposure seen in humans administered the maintenance dose. Hepatic hemangiomas were increased in female mice at 300 mg/kg, at an exposure similar to the maintenance dose. Hepatoblastoma were increased in male mice at 100 mg/kg, about 0.4 times the systemic exposures based on AUC comparisons. Thyroid follicular cell adenomas were observed in male and female rats at doses as low as 60 mg/kg in male rats (about 0.2 times the human clinical maintenance dose). The relevance of the rat thyroid tumors to human carcinogenic risk remains unclear.A significant increase in the incidence of skin fibromas was seen in male rats at 300 mg/kg, exposures 0.8 times the human exposure at the human clinical maintenance dose. Uterine adenocarcinomas were observed in female rats at 200 mg/kg, at systemic exposures similar to the human exposure at the human clinical maintenance dose.No mutagenic or clastogenic effects were detected in the in vitro bacterial reverse mutation assay and the in vivo bone marrow micronucleus assay in rats.Oral administration of isavuconazonium sulfate did not affect the fertility in male or female rats treated at doses up to 90 mg/kg/day (approximately 0.3 times the systemic exposure at the human clinical maintenance dose).

OVERDOSAGE SECTION.

10 OVERDOSAGE. During clinical studies, total daily CRESEMBA doses higher than the recommended dose regimen were associated with an increased rate of adverse reactions. At supratherapeutic doses (three times the recommended maintenance dose) evaluated in thorough QT study, there were proportionally more treatment-emergent adverse reactions than in the therapeutic dose group (maintenance dose) for the following: headache, dizziness, paresthesia, somnolence, disturbance in attention, dysgeusia, dry mouth, diarrhea, oral hypoesthesia, vomiting, hot flush, anxiety, restlessness, palpitations, tachycardia, photophobia and arthralgia. Treatment-emergent adverse reactions leading to discontinuation of study drug occurred in of 39 (17.9%) subjects in the supratherapeutic dose group.Isavuconazole is not removed by hemodialysis. There is no specific antidote for isavuconazole. Treatment should be supportive with appropriate monitoring.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Package/Label Display Panel CRESEMBA capsules 186 mg blister carton label. NDC 0469-0520-14CRESEMBA(R) (isavuconazonium sulfate) capsules186 mgequivalent to 100 mg isavuconazoleUnit dose blister14 CapsulesRx Only. Cresemba (isavuconazonium sulfate) capsules 186 mg blister carton label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and efficacy of CRESEMBA in pediatric patients less than 18 years of age have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Pharmacokinetic/Pharmacodynamic Relationship. In patients treated with CRESEMBA for invasive aspergillosis in controlled trial, there was no significant association between plasma AUC or plasma isavuconazole concentration and efficacy.. Cardiac Electrophysiology. The effect on QTc interval of multiple doses of CRESEMBA capsules was evaluated. CRESEMBA was administered as capsules (equivalent to 200 mg isavuconazole) three times daily on days and followed by either capsules or capsules (equivalent to 600 mg isavuconazole) once daily for 13 days in randomized, placebo- and active-controlled (moxifloxacin 400 mg single-dose), four-treatment-arm, parallel study in 160 healthy subjects.Isavuconazole resulted in dose-related shortening of the QTc interval. For the 2-capsule dosing regimen, the least squares mean (LSM) difference from placebo was -13.1 msec at hours postdose [90% CI: -17.1, -9.1 msec]. Increasing the dose to capsules resulted in an LSM difference from placebo of -24.6 msec at hours postdose [90% CI: -28.7, -20.4]. CRESEMBA was not evaluated in combination with other drugs that reduce the QTc interval, so the additive effects are not known.

PHARMACOKINETICS SECTION.

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 5). Based on population pharmacokinetics analysis of healthy subjects and patients, the mean plasma half-life of isavuconazole was 130 hours and the mean volume of distribution (Vss) was approximately 450 following intravenous administration.Table 5. Steady State Pharmacokinetic Parameters of Isavuconazole Following Administration of CRESEMBA CapsulesParameterCRESEMBA CapsulesEach capsule contains the equivalent of 100 mg of isavuconazole.(n 37)CRESEMBA Capsules(n 32)Cmax (ng/mL)MeanSDCV %74991893.325.2200283584.317.9tmax (h)MedianRange3.0002.0 4.04.0002.0 4.0AUC (hong/mL)MeanSDCV %12140235768.829.535280572018.520.4. Absorption. After oral administration of CRESEMBA in healthy volunteers, the active moiety, isavuconazole, generally reaches maximum plasma concentrations (Cmax) hours to 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 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 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 6).Table 6. Statistical Comparison of Plasma Pharmacokinetics of Isavuconazole Following Single Oral Dose Administration of 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 Subjects Under Fasted Conditions CRESEMBA IV Solution via NG TubeCRESEMBA Oral CapsulesNG Tube/Oral CapsulePharmacokinetic ParameterNMean (%CV)NMean (%CV)GMR (90% CI)Cmax (ng/mL)132295 (23.6)132185 (26.7)105.34 (89-124)AUC0-72hr (hr.ng/mL)1334885 (22.1)1335777 (24.6)97.81 (93-103)AUC0- (hr.ng/mL)1298142 (44.5)12100050 (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 high-fat meal reduced isavuconazole Cmax by 9% and increased AUC by 9%. CRESEMBA can be taken with or without food. Distribution. Isavuconazole is extensively distributed with mean steady state volume of distribution (Vss) of approximately 450 L. Isavuconazole is highly protein bound (greater than 99%), predominantly to albumin.. Metabolism. In in vitro studies isavuconazonium sulfate is rapidly hydrolyzed in blood to isavuconazole by esterases, predominantly by butylcholinesterase. Isavuconazole is substrate of cytochrome P450 enzymes 3A4 and 3A5.Following single doses of [cyano 14C] isavuconazonium and [pyridinylmethyl 14C] isavuconazonium in humans, in addition to the active moiety (isavuconazole) and the inactive cleavage product, 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, 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 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 CRESEMBA in pediatric patients have not been evaluated.. Race. 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 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 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 difference in AUC for elderly females, see Geriatric section above. No dose adjustment is required based on gender.. Renal Impairment. Total isavuconazole AUC and Cmax were not affected to 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. dose adjustment is not warranted in patients with ESRD.. Hepatic Impairment. After 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 group and the Child-Pugh Class group, respectively, relative to 32 age and weight-matched healthy subjects with normal hepatic function. Mean Cmax was 2% lower in the Child-Pugh Class group and 30% lower in the Child-Pugh Class 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 StudiesIsavuconazole is substrate of CYP3A4 and CYP3A5. In vitro, isavuconazole is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Isavuconazole is also an inhibitor of P-gp-, BCRP- and OCT2-mediated drug transporters. In vitro, isavuconazole is also an inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9.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 strong CYP3A4 inhibitor, ketoconazole increased the isavuconazole Cmax by 9% and isavuconazole AUC by 422% after multiple-dose administration of ketoconazole (200 mg twice daily) for 24 days and single-dose of CRESEMBA equivalent to 200 mg of isavuconazole. Isavuconazole is sensitive CYP3A4 substrate and use with strong CYP3A4 inhibitors are contraindicated per Section and Figure 1.Lopinavir/Ritonavir: Lopinavir/ritonavir (400 mg/100 mg twice daily) increased the Cmax 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 Cmax 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 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 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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on findings from animal studies, CRESEMBA may cause fetal harm when administered to pregnant woman. There are no available human data on the use of CRESEMBA in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, perinatal mortality was increased in the offspring of pregnant rats dosed orally with isavuconazonium sulfate at approximately 0.5 times the clinical exposure during pregnancy through the weaning period. In animal studies when isavuconazonium chloride was administered by oral gavage to pregnant rats and rabbits during organogenesis at exposures corresponding to less than the human maintenance dose, increases in the incidences of multiple skeletal abnormalities, including rudimentary cervical ribs and fused zygomatic arches, were observed (see Data). Advise pregnant women of the potential risk to fetus [see Warnings and Precautions (5.4)].The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.DataAnimal DataIsavuconazonium chloride administration during organogenesis (gestational days 6-17 in rats and gestational days 6-18 in rabbits) was associated with dose-related increases in the incidences of rudimentary cervical ribs in rats and rabbits at 30 and 45 mg/kg, respectively, equivalent to about 0.2 and 0.1 times of the clinical exposure 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 0.2 times the human AUC. Skeletal abnormalities have also been observed in embryo-fetal development studies of other azole antifungal agents.Isavuconazonium sulfate increased perinatal mortality in the pups when orally administered to pregnant rats during pregnancy and lactation (gestational day through postpartum day 20) at doses up to 90 mg/kg/day (approximately 0.5 times the clinical exposure based on AUC comparison). No effect on the duration of pregnancy or delivery was seen in the pups at this same dose.

RECENT MAJOR CHANGES SECTION.

Dosage and Administration, Preparation Instructions for the Nasogastric Tube Administration of the Injection Formulation (2.5) 04/2021 Warnings and Precautions, Hypersensitivity Reactions (5.3) 12/2021.

REFERENCES SECTION.

15 REFERENCES 1.DePauw, B., Walsh, T.J., Donnelly, J.P., et al. (2008) Revised Definitions of Invasive Fungal Disease from the European Organization for Research and Treatment of Cancer Invasive Fungal Infections Quadrature Group and National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) consensus group. Clinical Infectious Diseases 46:1813-1821.. 1.DePauw, B., Walsh, T.J., Donnelly, J.P., et al. (2008) Revised Definitions of Invasive Fungal Disease from the European Organization for Research and Treatment of Cancer Invasive Fungal Infections Quadrature Group and National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) consensus group. Clinical Infectious Diseases 46:1813-1821.

SPL PATIENT PACKAGE INSERT SECTION.

Patient InformationCRESEMBA(R) (Cre sem bah)(isavuconazonium sulfate)capsules, for oral use CRESEMBA(R) (Cre sem bah) (isavuconazonium sulfate)for injection, for intravenous useRead this Patient Information before you start taking CRESEMBA and each time you get refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.What is CRESEMBACRESEMBA is prescription medicine used to treat people 18 years of age and older with certain types of fungal infections in the blood or body called aspergillosis, and mucormycosis (zygomycosis). It is not known if CRESEMBA is safe and effective in children under 18 years of age.Who should not take CRESEMBADo not take CRESEMBA if you:oare allergic to CRESEMBA or any of the ingredients. See the end of this Patient Information leaflet for complete list of ingredients in CRESEMBA.oare taking any of the following medicines:oketoconazoleohigh-dose ritonavirorifampinocarbamazepineoSt. Johns wort (herbal supplement)olong-acting barbituratesohave genetic problem that affects the electrical system of the heart (familial short QT syndrome)Talk to your healthcare provider or pharmacist if you are not sure if you are taking any of these medicines or have any of the conditions listed above.Do not start taking new medicines without talking to your healthcare provider or pharmacist.Before you take CRESEMBA, tell your healthcare provider about all of your medical conditions, including if you:ohave or ever had an abnormal heart rate or rhythm. Your healthcare provider may order test to check your heart (ECG) before starting CRESEMBA.ohave liver problems. Your healthcare provider may do blood tests to make sure you can take CRESEMBA.ohave ever had an allergic reaction to other antifungal medicines such as ketoconazole, fluconazole, itraconazole, voriconazole or posaconazole.oare pregnant or plan to become pregnant. CRESEMBA may harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant. Women who can become pregnant should use effective birth control while taking CRESEMBA and for 28 days after the last CRESEMBA dose. Talk to your healthcare provider about birth control methods that may be right for you. oare breastfeeding or plan to breastfeed. CRESEMBA can pass into your breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take CRESEMBA. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.CRESEMBA may affect the way other medicines work, and other medicines may affect how CRESEMBA works and can cause side effects.Ask your healthcare provider or pharmacist for list of these medicines, if you are not sure.Know the medicines you take. Keep list of them with you to show your healthcare provider and pharmacist when you get new medicine.How should take CRESEMBA capsulesoTake CRESEMBA exactly as your healthcare provider tells you to take it.oDo not stop taking CRESEMBA until your healthcare provider tells you to.oIf you take too much CRESEMBA, call your healthcare provider.oCRESEMBA capsules can be taken with or without food.oSwallow CRESEMBA capsules whole. Do not chew, crush, dissolve, or open the capsules. Instructions on opening CRESEMBA capsules blister packaging:CRESEMBA capsules are in child-resistant blister packaging. Each blister section contains two pockets: one pocket for the CRESEMBA capsule and one pocket for the desiccant to protect the capsule from moisture (located to the left of the capsule).oOnly open the blister packaging at time of use. Make sure only the CRESEMBA capsule pocket is opened.oDo not puncture the pocket containing the desiccant. oDo not swallow or use the desiccant.What are the possible side effects of CRESEMBACRESEMBA may cause serious side effects, including:oliver problems. Liver problems can happen in some people taking CRESEMBA. Some people who also have other serious medical problems may get severe liver problems which can lead to hepatitis, gallbladder problems, liver failure or death. Your healthcare provider should do blood tests to check your liver before you start and while you are taking CRESEMBA. Call your healthcare provider right away if you have any of the following symptoms of liver problems:oitchy skinonausea or vomitingoyellowing of your eyesofeeling very tiredoflu-like symptomsoinfusion reactions. Infusion reactions can happen in people receiving CRESEMBA intravenously. If an infusion reaction happens, your infusion will be stopped. Symptoms of an infusion reaction may include:olow blood pressureodifficulty breathingochillsodizzinessonumbness and tinglingochanges in your sense of touch (hypoesthesia)osevere allergic reactions.oSevere allergic reactions including death can happen in some people taking CRESEMBA. Symptoms of severe allergic reaction may include: oswelling of your face, lips, mouth, or tongueowheezingoskin rash redness, or swelling ofast heartbeat or pounding in your chestotrouble breathingosevere itchingodizziness or faintingosweating Stop taking CRESEMBA and call your healthcare provider or go to the nearest hospital emergency room right away if you have any of the symptoms listed above.odrug interactions with cyclosporine, sirolimus, or tacrolimus. If you take CRESEMBA with cyclosporine, sirolimus, or tacrolimus, your blood levels of cyclosporine, sirolimus, or tacrolimus may increase. Serious side effects can happen in your kidney or brain if you have high levels of cyclosporine, sirolimus, or tacrolimus in your blood. Your healthcare provider should do blood tests to check your levels of cyclosporine, sirolimus, or tacrolimus if you are taking these medicines while taking CRESEMBA. Tell your healthcare provider right away if you have swelling in your arm or leg or shortness of breath.omedicine interactions. Taking CRESEMBA with some other medicines may affect the way other medicines work causing serious side effects. Other medicines may affect the way CRESEMBA works, causing serious side effects. Tell your healthcare provider about all the medicines you take.The most common side effects of CRESEMBA include:onauseaovomitingodiarrheaoheadacheochanges in the level of liver enzyme in your bloodolow potassiumoconstipationoshortness of breathocoughoswelling of arms or legsoback painTell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of CRESEMBA. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store CRESEMBA capsulesoStore CRESEMBA at room temperature between 68F to 77F (20C to 25C).oKeep CRESEMBA in the original package and protect it from moisture.oDo not remove CRESEMBA from original packaging.oSafely throw away medicine that is out of date or no longer needed.Keep CRESEMBA and all medicines out of the reach of children.General information about the safe and effective use of CRESEMBA.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use CRESEMBA for condition for which it was not prescribed. Do not give CRESEMBA to other people, even if they have the same symptoms that you have. It may harm them. This Patient Information leaflet summarizes the most important information about CRESEMBA. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about CRESEMBA that is written for health professionals.What are the ingredients of CRESEMBAActive ingredient: isavuconazonium sulfate.Inactive ingredients: magnesium citrate, microcrystalline cellulose, talc, colloidal silicon dioxide, stearic acid, hypromellose, red iron oxide, titanium dioxide, purified water, gellan gum, potassium acetate, disodium edetate, sodium laurylsulfate, shellac, propylene glycol, strong ammonia solution, potassium hydroxide, black iron oxide. Marketed and Distributed by: Astellas Pharma US, Inc. Northbrook, IL 60062312370-ISA-USACRESEMBA is registered trademark of Astellas US LLC.Licensed from: Basilea Pharmaceutica International Ltd.For more information go to www.CRESEMBA.com or call 1-800-727-7003.This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: 12/2021. oare allergic to CRESEMBA or any of the ingredients. See the end of this Patient Information leaflet for complete list of ingredients in CRESEMBA.. oare taking any of the following medicines:. oketoconazole. ohigh-dose ritonavir. orifampin. ocarbamazepine. oSt. Johns wort (herbal supplement). olong-acting barbiturates. ohave genetic problem that affects the electrical system of the heart (familial short QT syndrome). ohave or ever had an abnormal heart rate or rhythm. Your healthcare provider may order test to check your heart (ECG) before starting CRESEMBA.. ohave liver problems. Your healthcare provider may do blood tests to make sure you can take CRESEMBA.. ohave ever had an allergic reaction to other antifungal medicines such as ketoconazole, fluconazole, itraconazole, voriconazole or posaconazole.. oare pregnant or plan to become pregnant. CRESEMBA may harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant. Women who can become pregnant should use effective birth control while taking CRESEMBA and for 28 days after the last CRESEMBA dose. Talk to your healthcare provider about birth control methods that may be right for you. oare breastfeeding or plan to breastfeed. CRESEMBA can pass into your breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take CRESEMBA. oTake CRESEMBA exactly as your healthcare provider tells you to take it.. oDo not stop taking CRESEMBA until your healthcare provider tells you to.. oIf you take too much CRESEMBA, call your healthcare provider.. oCRESEMBA capsules can be taken with or without food.. oSwallow CRESEMBA capsules whole. Do not chew, crush, dissolve, or open the capsules. oOnly open the blister packaging at time of use. Make sure only the CRESEMBA capsule pocket is opened.. oDo not puncture the pocket containing the desiccant. oDo not swallow or use the desiccant.. oliver problems. Liver problems can happen in some people taking CRESEMBA. Some people who also have other serious medical problems may get severe liver problems which can lead to hepatitis, gallbladder problems, liver failure or death. Your healthcare provider should do blood tests to check your liver before you start and while you are taking CRESEMBA. Call your healthcare provider right away if you have any of the following symptoms of liver problems:. oitchy skin. onausea or vomiting. oyellowing of your eyes. ofeeling very tired. oflu-like symptoms. oinfusion reactions. Infusion reactions can happen in people receiving CRESEMBA intravenously. If an infusion reaction happens, your infusion will be stopped. Symptoms of an infusion reaction may include:. olow blood pressure. odifficulty breathing. ochills. odizziness. onumbness and tingling. ochanges in your sense of touch (hypoesthesia). osevere allergic reactions.. oSevere allergic reactions including death can happen in some people taking CRESEMBA. Symptoms of severe allergic reaction may include: oswelling of your face, lips, mouth, or tongue. owheezing. oskin rash redness, or swelling ofast heartbeat or pounding in your chest. otrouble breathing. osevere itching. odizziness or fainting. osweating. odrug interactions with cyclosporine, sirolimus, or tacrolimus. If you take CRESEMBA with cyclosporine, sirolimus, or tacrolimus, your blood levels of cyclosporine, sirolimus, or tacrolimus may increase. Serious side effects can happen in your kidney or brain if you have high levels of cyclosporine, sirolimus, or tacrolimus in your blood. Your healthcare provider should do blood tests to check your levels of cyclosporine, sirolimus, or tacrolimus if you are taking these medicines while taking CRESEMBA. Tell your healthcare provider right away if you have swelling in your arm or leg or shortness of breath.. omedicine interactions. Taking CRESEMBA with some other medicines may affect the way other medicines work causing serious side effects. Other medicines may affect the way CRESEMBA works, causing serious side effects. Tell your healthcare provider about all the medicines you take.. onausea. ovomiting. odiarrhea. oheadache. ochanges in the level of liver enzyme in your blood. olow potassium. oconstipation. oshortness of breath. ocough. oswelling of arms or legs. oback pain. oStore CRESEMBA at room temperature between 68F to 77F (20C to 25C).. oKeep CRESEMBA in the original package and protect it from moisture.. oDo not remove CRESEMBA from original packaging.. oSafely throw away medicine that is out of date or no longer needed.

SPL UNCLASSIFIED SECTION.

1.1 Invasive Aspergillosis. CRESEMBA(R) is an azole antifungal indicated for patients 18 years of age and older for the treatment of invasive aspergillosis [see Clinical Studies (14.1) and Clinical Pharmacology (12.4)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. oBreastfeeding should be discontinued during treatment with CRESEMBA. (8.2)oUse in patients with severe hepatic impairment only when the benefits outweigh the risks; clinical monitoring for CRESEMBA-related adverse reactions is recommended. (8.7). oBreastfeeding should be discontinued during treatment with CRESEMBA. (8.2). oUse in patients with severe hepatic impairment only when the benefits outweigh the risks; clinical monitoring for CRESEMBA-related adverse reactions is recommended. (8.7). 8.1 Pregnancy. Risk SummaryBased on findings from animal studies, CRESEMBA may cause fetal harm when administered to pregnant woman. There are no available human data on the use of CRESEMBA in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, perinatal mortality was increased in the offspring of pregnant rats dosed orally with isavuconazonium sulfate at approximately 0.5 times the clinical exposure during pregnancy through the weaning period. In animal studies when isavuconazonium chloride was administered by oral gavage to pregnant rats and rabbits during organogenesis at exposures corresponding to less than the human maintenance dose, increases in the incidences of multiple skeletal abnormalities, including rudimentary cervical ribs and fused zygomatic arches, were observed (see Data). Advise pregnant women of the potential risk to fetus [see Warnings and Precautions (5.4)].The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.DataAnimal DataIsavuconazonium chloride administration during organogenesis (gestational days 6-17 in rats and gestational days 6-18 in rabbits) was associated with dose-related increases in the incidences of rudimentary cervical ribs in rats and rabbits at 30 and 45 mg/kg, respectively, equivalent to about 0.2 and 0.1 times of the clinical exposure 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 0.2 times the human AUC. Skeletal abnormalities have also been observed in embryo-fetal development studies of other azole antifungal agents.Isavuconazonium sulfate increased perinatal mortality in the pups when orally administered to pregnant rats during pregnancy and lactation (gestational day through postpartum day 20) at doses up to 90 mg/kg/day (approximately 0.5 times the clinical exposure based on AUC comparison). No effect on the duration of pregnancy or delivery was seen in the pups at this same dose.. 8.2 Lactation Risk SummaryThere are no data on the presence of isavuconazole in human milk, the effects on the breastfed infant or the effects on milk production. Isavuconazole was present in the milk of lactating rats following intravenous administration. When drug is present in animal milk, it is likely that the drug will be present in human milk. Therefore, breastfeeding should be discontinued during treatment with CRESEMBA.. 8.3 Females and Males of Reproductive Potential ContraceptionCRESEMBA may cause embryo-fetal harm when administered to pregnant women [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1)]. Advise female patients of reproductive potential to use effective contraception during treatment with CRESEMBA and for 28 days after the final dose.. 8.4 Pediatric Use. The safety and efficacy of CRESEMBA in pediatric patients less than 18 years of age have not been established.. 8.5 Geriatric Use. Of the 547 patients who received CRESEMBA in the Phase and trials, 86 (16%) of patients were greater than 65 years of age and 20 (4%) were greater than 75 years of age. The pharmacokinetics of isavuconazole are comparable in young and elderly subjects (65 years of age and older) [see Clinical Pharmacology (12.3)]. No dose adjustment of CRESEMBA is needed in elderly patients.. 8.6 Renal Impairment. Of the 403 patients who received CRESEMBA in the Phase trials, 79 (20%) of patients had an estimated glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2. No dose adjustment is needed in patients with mild, moderate, or severe renal impairment, including those patients with End-Stage Renal Disease (ESRD) [see Clinical Pharmacology (12.3)].. 8.7 Hepatic Impairment. No dose adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh Class and B) [see Clinical Pharmacology (12.3)]. CRESEMBA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and should be used in these patients only when the benefits outweigh the risks. Clinical monitoring for CRESEMBA-related adverse reactions is recommended when treating patients with severe hepatic impairment [see Warnings and Precautions (5.1)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oHepatic Adverse Drug Reactions: Serious hepatic reactions have been reported. Evaluate liver-related laboratory tests at the start and during the course of CRESEMBA therapy. (5.1)oInfusion-related reactions were reported during intravenous administration of CRESEMBA. Discontinue the infusion if these reactions occur. (5.2)oHypersensitivity 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. (5.3)oEmbryo-Fetal Toxicity: CRESEMBA may cause fetal harm when administered to 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)oDrug Interactions: Review patients concomitant medications. Several drugs may significantly alter isavuconazole concentrations. Isavuconazole may alter concentrations of several drugs. (5.5, 7, 12.3)oDrug Particulates: Intravenous formulation may form insoluble particulates following reconstitution. Administer CRESEMBA through an in-line filter. (2.4, 5.6). oHepatic Adverse Drug Reactions: Serious hepatic reactions have been reported. Evaluate liver-related laboratory tests at the start and during the course of CRESEMBA therapy. (5.1). oInfusion-related reactions were reported during intravenous administration of CRESEMBA. Discontinue the infusion if these reactions occur. (5.2). oHypersensitivity 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. (5.3). oEmbryo-Fetal Toxicity: CRESEMBA may cause fetal harm when administered to 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). oDrug Interactions: Review patients concomitant medications. Several drugs may significantly alter isavuconazole concentrations. Isavuconazole may alter concentrations of several drugs. (5.5, 7, 12.3). oDrug Particulates: Intravenous formulation may form insoluble particulates following reconstitution. Administer CRESEMBA through an in-line filter. (2.4, 5.6). 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 [see Adverse Reactions (6.1)].. 5.2 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 [see Adverse Reactions (6.1)].. 5.3 Hypersensitivity Reactions. Anaphylactic ReactionsAnaphylactic 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 ReactionsSevere skin reactions, such as Stevens-Johnson syndrome, have been reported during treatment with other azole antifungal agents.Discontinue CRESEMBA if 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.. 5.4 Embryo-Fetal Toxicity. Based on findings from animal reproduction studies, CRESEMBA may cause fetal harm when administered to pregnant woman. Advise pregnant women of the potential risk to 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 [see Use in Specific Populations (8.1)].Advise females of reproductive potential to use an effective method of contraception during treatment with CRESEMBA and for 28 days after the final dose [see Use in Specific Populations (8.3)].. 5.5 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. Johns wort, or long acting barbiturates is contraindicated [see Contraindications (4) and Drug Interactions (7)].. 5.6 Drug Particulates. Following dilution, CRESEMBA intravenous formulation may form precipitate from the insoluble isavuconazole. Administer CRESEMBA through an in-line filter [see Dosage and Administration (2.4)].