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The following are discussed in more detail in other sections of the labeling:

Hepatic Adverse Drug Reactions

Infusion-Related Reactions

Hypersensitivity Reactions

Embryo-Fetal Toxicity

Adult Patients: The most frequent adverse reactions in adult patients were nausea, vomiting, diarrhea, headache, elevated liver chemistry tests, hypokalemia, constipation, dyspnea, cough, peripheral edema, and back pain.

Pediatric Patients: The most frequent adverse reactions in pediatric patients were diarrhea, abdominal pain, vomiting, elevated liver chemistry tests, rash, nausea, pruritus, and headache. To report SUSPECTED ADVERSE REACTIONS, contact Astellas Pharma US, Inc. at 1-800-727-7003 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical

Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of CRESEMBA cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials Experience in Adult Patients A total of 403 adult patients were exposed to CRESEMBA in two clinical trials. The most frequently reported adverse reactions among CRESEMBA-treated patients were nausea (26%), vomiting (25%), diarrhea (22%), headache (17%), elevated liver chemistry tests (16%), hypokalemia (14%), constipation (13%), dyspnea (12%), cough (12%), peripheral edema (11%), and back pain (10%). Serious adverse reactions occurred in 223/403 (55%) of patients and 56/403 (14%) of patients permanently discontinued treatment with CRESEMBA due to an adverse reaction in the two trials. The adverse reactions which most often led to permanent discontinuation of CRESEMBA therapy during the clinical trials were confusional state (0.7%), acute renal failure (0.7%), increased blood bilirubin (0.5%), convulsion (0.5%), dyspnea (0.5%), epilepsy (0.5%), respiratory failure (0.5%), and vomiting (0.5%). Patients in the clinical trials were immunocompromised with underlying conditions including hematological malignancy, neutropenia post-chemotherapy, graft-versus-host disease, and hematopoietic stem cell transplant. The patient population was 61% male, had a mean age of 51 years (range 17-92, including 85 patients aged greater than 65 years), and was 79% White and 3% Black. One hundred forty-four patients had a duration of CRESEMBA therapy of greater than 12 weeks, with 52 patients receiving CRESEMBA for over six months. In Trial 1, a randomized, double-blind, active-controlled clinical trial for treatment of invasive aspergillosis, treatment‑emergent adverse reactions occurred in 247/257 (96%), and 255/259 (99%) patients in the CRESEMBA and voriconazole treatment groups, respectively. Adverse reactions resulting in permanent discontinuation were reported in 37 (14%) CRESEMBA-treated patients and 59 (23%) voriconazole-treated patients. Table 3 includes selected adverse reactions which were reported at an incidence of ≥ 5% during CRESEMBA therapy in Trial 1. In Trial 2, an open-label, non-comparative trial of CRESEMBA in patients with invasive aspergillosis and renal impairment or invasive mucormycosis, adverse reactions occurred in 139/146 (95%) of patients in the CRESEMBA treatment group. Adverse reactions resulting in permanent discontinuation were reported in 19 (13%) CRESEMBA‑treated patients. The frequencies and types of adverse reactions observed in CRESEMBA-treated patients were similar between Trial 1 and Trial 2. Table 3. Selected Adverse Reactions with Rates of 5% or Greater in CRESEMBA-treated Patients in Trial 1 System Organ Class Adverse Reactions Trial 1 CRESEMBA (N=257) n (%) Voriconazole (N=259) n (%) Gastrointestinal disorders Nausea 71 78 Vomiting 64 73 Diarrhea 61 60 Abdominal pain 43 59 Constipation 36 54 Dyspepsia 16 14 General disorders and administration site conditions Edema peripheral 39 46 Fatigue 27 18 Chest pain 23 16 Injection site reaction 16 4 Hepatobiliary disorders Elevated liver laboratory tests Elevated liver laboratory tests include reactions of increased alanine aminotransferase, aspartate aminotransferase, blood alkaline phosphatase, blood bilirubin, and gamma-glutamyl transferase. 44 63 Metabolism and nutrition disorders Hypokalemia 49 58 Decreased appetite 22 28 Hypomagnesemia 14 27 Musculoskeletal and connective tissue disorders Back pain 26 19 Nervous system disorders Headache 43 38 Psychiatric disorders Insomnia 27 25 Delirium Delirium includes adverse reactions of agitation, confusional state, delirium, disorientation, and mental status changes. 22 30 Anxiety 21 18 Renal and urinary disorders Renal failure 26 21 Respiratory, thoracic and mediastinal disorders Dyspnea 44 35 Acute respiratory failure 19 22 Skin and subcutaneous tissue disorders Rash 22 36 Pruritus 21 15 Vascular disorders Hypotension 21 28 The following adverse reactions occurred in less than 5% of all CRESEMBA-treated patients in Trial 1 or 2. The list does not include reactions presented in Table 3. This listing includes adverse reactions where a causal relationship to CRESEMBA cannot be ruled out or those which may help the physician in managing the risks to the patients.

Blood and lymphatic system disorders: agranulocytosis, leukopenia, pancytopenia

Cardiac disorders: atrial fibrillation, atrial flutter, bradycardia, reduced QT interval on electrocardiogram, palpitations, supraventricular extrasystoles, supraventricular tachycardia, ventricular extrasystoles, cardiac arrest

Ear and labyrinth disorders: tinnitus, vertigo

Eye disorders: optic neuropathy

Gastrointestinal disorders: abdominal distension, gastritis, gingivitis, stomatitis

General disorders and administration site conditions: catheter thrombosis, malaise, chills

Hepatobiliary disorders: cholecystitis, cholelithiasis, hepatitis, hepatomegaly, hepatic failure

Immune system disorders: hypersensitivity

Injury, poisoning and procedural complications: fall

Metabolism and nutrition disorders: hypoalbuminemia, hypoglycemia, hyponatremia

Musculoskeletal and connective tissue disorders: myositis, bone pain, neck pain

Nervous system disorders: convulsion, dysgeusia, encephalopathy, hypoesthesia, migraine, peripheral neuropathy, paresthesia, somnolence, stupor, syncope, tremor

Psychiatric disorders: confusion, hallucination, depression

Renal and urinary disorders: hematuria, proteinuria

Respiratory, thoracic and mediastinal disorders: bronchospasm, tachypnea

Skin and subcutaneous tissue disorders: alopecia, dermatitis, exfoliative dermatitis, erythema, petechiae, urticaria

Vascular disorders: thrombophlebitis Laboratory Effects In Trial 1, elevated liver transaminases (alanine aminotransferase or aspartate aminotransferase) greater than three times the upper limit of normal were reported at the end of study treatment in 4.4% of patients who received CRESEMBA. Elevations of liver transaminases greater than ten times the upper limit of normal developed in 1.2% of patients who received CRESEMBA. Clinical Trials Experience in Pediatric Patients The clinical safety of CRESEMBA was assessed in 77 pediatric patients who received at least one dose of intravenous or oral CRESEMBA in two uncontrolled studies. Fifteen (19.5%) subjects were in the 1 to < 6 years old cohort, 30 subjects (39.0%) were in the 6 to < 12 years old cohort, and 32 subjects (41.6%) were in the 12 to < 18 years old cohort. The duration of treatment ranged from 1 to 181 days with a median duration of treatment of 15 days. The most frequently reported adverse reactions were diarrhea (26%), abdominal pain (23%), vomiting (21%), elevated liver chemistry tests (18%), rash (14%), nausea (13%), pruritus (13%) and headache (12%). In general, adverse reactions (including serious adverse reactions and adverse reactions leading to permanent discontinuation of CRESEMBA) were similar to those reported in adults.

6.2 Post-Marketing

Experience The following additional adverse reactions have been identified during post-approval use of CRESEMBA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Immune system disorders: anaphylactic reaction