Cresemba

1 INDICATIONS AND USAGE CRESEMBA ® is an azole antifungal indicated for the treatment of: Invasive aspergillosis and Invasive mucormycosis as follows: • CRESEMBA for injection : adults and pediatric patients 1 year of age and older • CRESEMBA capsules : adults and pediatric patients 6 years of age and older who weigh 16 kilograms (kg) and greater

1.1Invasive Aspergillosis

CRESEMBA ® is indicated for the treatment of invasive aspergillosis as follows: CRESEMBA for injection : adults and pediatric patients 1 year of age and older CRESEMBA capsules : adults and pediatric patients 6 years of age and older who weigh 16 kilograms (kg) and greater

1.2Invasive Mucormycosis

CRESEMBA is indicated for the treatment of invasive mucormycosis as follows: CRESEMBA for injection : adults and pediatric patients 1 year of age and older CRESEMBA capsules : adults and pediatric patients 6 years of age and older who weigh 16 kg and greater , Clinical Studies and Clinical Pharmacology ( 12.3 , 12.4 )]

1.3Usage 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.

Important Administration Instructions: • CRESEMBA for injection is intended for use in patients who are 1 year of age and older ( 2.1 , 2.3 ). • CRESEMBA for injection via nasogastric (NG) tube administration is intended for use by patients who are 6 years of age and older and weighing 16 kg and greater. ( 2.1 , 2.6 ). • CRESEMBA for injection must be administered through an in-line filter over a minimum of 1 hour. ( 2.1 , 2.5 ). • CRESEMBA capsules are intended for use in patients who are 6 years of age and older and weighing 16 kg and greater ( 2.1 , 2.3 ). • CRESEMBA capsules can be taken with or without food.. Recommended Dosage in Adult Patients: Recommended Dosage for CRESEMBA in Adult Patients Dosage Form Loading Dose Maintenance Dose Start maintenance doses 12 to 24 hours after the last loading dose CRESEMBA for Injection, 372 mg/vial 372 mg of isavuconazonium sulfate per vial One reconstituted vial (372 mg) intravenously every 8 hours for 6 doses (48 hours) One reconstituted vial (372 mg) intravenously once daily CRESEMBA Capsules, 186 mg 186 mg of isavuconazonium sulfate per capsule Two 186 mg capsules (372 mg) orally every 8 hours for 6 doses (48 hours) Two 186 mg capsules (372 mg) orally once daily CRESEMBA Capsules, 74.5 mg 74.5 mg of isavuconazonium sulfate per capsule Five 74.5 mg capsules (372 mg) orally every 8 hours for 6 doses (48 hours) Five 74.5 mg capsules (372 mg) orally once daily Recommended Dosage in Pediatric Patients: • The maximum of any individual loading or daily maintenance dose to be administered to any pediatric patient is 372 mg of CRESEMBA. Recommended Dosage for CRESEMBA in Pediatric Patients Dosage Form Age Body Weight (kg) Loading Dose Maintenance Dose Start maintenance doses 12 to 24 hours after the last loading dose CRESEMBA for Injection, 372 mg/vial 372 mg of isavuconazonium sulfate per vial 1 to less than 3 years of age less than 18 kg 15 mg/kg intravenously every 8 hours for 6 doses (48 hours) 15 mg/kg intravenously once daily 3 to less than 18 years of age less than 37 kg 10 mg/kg intravenously every 8 hours for 6 doses (48 hours) 10 mg/kg intravenously once daily greater than or equal to 37 kg One reconstituted vial (372 mg) intravenously every 8 hours for 6 doses (48 hours) One reconstituted vial (372 mg) intravenously once daily CRESEMBA Capsules, 74.5 mg 74.5 mg of isavuconazonium sulfate per capsule 6 to less than 18 years of age 16 kg to less than 18 kg Two capsules (149 mg) orally every 8 hours for 6 doses (48 hours) Two capsules (149 mg) orally once daily 18 kg to less than 25 kg Three capsules (223.5 mg) orally every 8 hours for 6 doses (48 hours) Three capsules (223.5 mg) orally once daily 25 kg to less than 32kg Four capsules (298 mg) orally every 8 hours for 6 doses (48 hours) Four capsules (298 mg) orally once daily greater than or equal to 32 kg Five 74.5 mg capsules (372 mg) orally every 8 hours for 6 doses (48 hours) Five 74.5 mg capsules (372 mg) orally once daily

2.1Important Administration Instructions for

CRESEMBA CRESEMBA for Injection • CRESEMBA for injection is intended for use in patients who are 1 year of age and older . • Intravenous formulation must be administered via an infusion set with an in-line filter (pore size 0.2 to 1.2 micron). • Infuse the intravenous formulation over a minimum of 1 hour in 250 mL of a compatible diluent, to reduce the risk for infusion-related reactions. Do not administer as an intravenous bolus injection. • Do not infuse CRESEMBA with other intravenous medications. • Flush intravenous lines with 0.9% sodium chloride injection, USP or 5% dextrose injection, USP prior to and after infusion of CRESEMBA. • After dilution of the intravenous formulation, avoid unnecessary vibration or vigorous shaking of the solution. Do not use a pneumatic transport system.

Nasogastric Tube Administration of CRESEMBA for Injection • CRESEMBA for injection via nasogastric (NG) tube administration is intended for use by patients who are 6 years of age and older and weighing 16 kg and greater . CRESEMBA Capsules • CRESEMBA capsules are intended for use in patients who are 6 years of age and older and weighing 16 kg and greater . • Switching between the intravenous and oral formulations of CRESEMBA is acceptable as bioequivalence has been demonstrated. Loading dose is not required when switching between formulations. • With oral administration, swallow CRESEMBA capsules whole. Do not chew, crush, dissolve, or open the capsules.

CRESEMBA capsules can be taken with or without food.

2.2Recommended Dosage and Administration in Adult Patients

Recommended dosage and administration of CRESEMBA for injection and capsules in adult patients is described in Table 1 below. CRESEMBA (isavuconazonium sulfate) is the prodrug of isavuconazole, an azole antifungal drug. Table 1. Recommended Dosage and Administration for CRESEMBA in Adult Patients Dosage Form Loading Dose Maintenance Dose Start maintenance doses 12 to 24 hours after the last loading dose.

CRESEMBA for Injection, 372 mg/vial 372 mg 372 mg of isavuconazonium sulfate is equivalent to 200 mg of isavuconazole. of isavuconazonium sulfate per vial One reconstituted vial (372 mg ) intravenously every 8 hours for 6 doses (48 hours) One reconstituted vial (372 mg ) intravenously once daily CRESEMBA Capsules, 186 mg 186 mg 186 mg of isavuconazonium sulfate is equivalent to 100 mg of isavuconazole. of isavuconazonium sulfate per capsule Two 186 mg capsules (372 mg ) orally every 8 hours for 6 doses (48 hours) Two 186 mg capsules (372 mg ) orally once daily CRESEMBA Capsules, 74.5 mg 74.5 mg 74.5 mg of isavuconazonium sulfate is equivalent to 40 mg of isavuconazole. of isavuconazonium sulfate per capsule Five 74.5 mg capsules (372 mg ) orally every 8 hours for 6 doses (48 hours) Five 74.5 mg capsules (372 mg ) orally once daily

2.3Recommended Dosage and Administration in Pediatric Patients

Recommended dosage and administration of CRESEMBA for injection and CRESEMBA capsules in pediatric patients is described in Table 2 below . The maximum of any individual loading or daily maintenance dose to be administered to any pediatric patient is 372 mg of CRESEMBA. Table 2. Recommended Dosage and Administration for CRESEMBA in Pediatric Patients Dosage Form Age Body Weight (kg) Loading Dose Maintenance Dose Start maintenance doses 12 to 24 hours after the last loading dose. CRESEMBA for Injection, 372 mg/vial 372 mg 372 mg of isavuconazonium sulfate is equivalent to 200 mg of isavuconazole. of isavuconazonium sulfate per vial 1 year to less than 3 years of age less than 18 kg 15 mg/kg intravenously every 8 hours for 6 doses (48 hours) 15 mg/kg intravenously once daily 3 years to less than 18 years of age less than 37 kg 10 mg/kg intravenously every 8 hours for 6 doses (48 hours) 10 mg/kg intravenously once daily greater than or equal to 37 kg One reconstituted vial (372 mg ) intravenously every 8 hours for 6 doses (48 hours) One reconstituted vial (372 mg ) intravenously once daily CRESEMBA Capsules, 74.5 mg 74.5 mg 74.5 mg of isavuconazonium sulfate is equivalent to 40 mg of isavuconazole. of isavuconazonium sulfate per capsule 6 to less than 18 years of age 16 kg to less than 18 kg Two capsules (149 mg) orally every 8 hours for 6 doses (48 hours) Two capsules (149 mg) orally once daily 18 kg to less than 25 kg Three capsules (223.5 mg) orally every 8 hours for 6 doses (48 hours) Three capsules (223.5 mg) orally once daily 25 kg to less than 32 kg Four capsules (298 mg) orally every 8 hours for 6 doses (48 hours) Four capsules (298 mg) orally once daily greater than or equal to 32 kg Five capsules Five 74.5 mg CRESEMBA capsules are equivalent to two 186 mg CRESEMBA capsules. (372 mg) orally every 8 hours for 6 doses (48 hours) Five capsules (372 mg) orally once daily

2.4Reconstitution Instructions for the

CRESEMBA for Injection Formulation Aseptic technique must be strictly observed in all handling since no preservative or bacteriostatic agent is present in CRESEMBA or in the materials specified for reconstitution. CRESEMBA is water soluble, preservative-free, sterile, and nonpyrogenic. • Reconstitute one vial of CRESEMBA by adding 5 mL water for injection, USP to the vial. The resultant solution will be 74.4 mg/mL of isavuconazonium sulfate. • Gently shake to dissolve the powder completely. • Visually inspect the reconstituted solution for particulate matter and discoloration.

Reconstituted CRESEMBA should be clear and free of visible particulate. • The reconstituted solution may be stored between 5°C to 25°C (41°F to 77°F) for a maximum of 1 hour prior to preparation of the patient intravenous infusion solution . • For nasogastric tube administration, the reconstituted solution should be administered within 1 hour of reconstitution . • Discard any unused portion of the reconstituted solution.

2.5Dilution and Preparation Instructions for the Intravenous Administration

of the CRESEMBA for Injection Formulation • Based on the adult or pediatric dosage regimen , remove the appropriate volume of the reconstituted solution (74.4 mg/mL of isavuconazonium sulfate) from the vial and add it to an infusion bag containing 250 mL of compatible diluent . A smaller volume infusion bag of compatible diluent may be used as long as the final concentration does not exceed approximately 1.5 mg isavuconazonium sulfate per mL. • The diluted solution may show visible translucent to white particulates of isavuconazole (which will be removed by in-line filtration). • Use gentle mixing or roll bag to minimize the formation of particulates. Avoid unnecessary vibration or vigorous shaking of the solution. • Apply in-line filter with a microporous membrane pore size of 0.2 to 1.2 micron and in-line filter reminder sticker to the infusion bag. • Do not use a pneumatic transport system. • The intravenous administration should be completed within 6 hours of dilution at room temperature. If this is not possible, immediately refrigerate (2°C to 8°C / 36°F to 46°F) the infusion solution after dilution and complete the infusion within 24 hours.

Do not freeze the infusion solution.

2.6Preparation Instructions for the Nasogastric Tube Administration

of the CRESEMBA for Injection Formulation CRESEMBA for injection can be administered through a nasogastric tube as follows: • Utilizing aseptic technique, reconstitute one vial of CRESEMBA for injection (equivalent to 200 mg isavuconazole) with 5 mL of water for injection, USP . • Based on the adult or pediatric (6 years of age to less than 18 years of age) CRESEMBA for injection dosage regimen , withdraw the appropriate volume of the reconstituted solution (74.4 mg/mL of isavuconazonium sulfate) from the vial using an appropriate syringe and needle. Discard the needle and cap the syringe. • To administer, remove the cap from the syringe containing the reconstituted solution and connect the syringe to the nasogastric (NG) tube to deliver the dose. After administering the dose, administer three 5 mL rinses to the NG tube with water . • Administer the reconstituted solution via the nasogastric tube within 1 hour of reconstitution.

Discard any unused portion of the reconstituted solution. • Do not administer CRESEMBA capsules through a nasogastric tube.

2.7Compatibility for the Injection Formulation

CRESEMBA for injection should only be administered with the following diluents: • 0.9% sodium chloride injection, USP • 5% dextrose injection, USP

5 WARNINGS AND PRECAUTIONS • Hepatic Adverse Drug Reactions: Serious hepatic reactions have been reported. Evaluate liver-related laboratory tests at the start and during the course of CRESEMBA therapy. • Infusion-related reactions were reported during intravenous administration of CRESEMBA. Discontinue the infusion if these reactions occur. • Hypersensitivity Reactions: Anaphylactic reactions, with fatal outcome, have been reported during treatment with CRESEMBA. Serious skin reactions, such as Stevens-Johnson syndrome, have been reported during treatment with other azole antifungal agents. Discontinue CRESEMBA if anaphylactic or serious skin reactions occur, and initiate supportive treatment as needed. • Embryo-Fetal Toxicity: CRESEMBA may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use an effective method of contraception. ( 5.4 , 8.1 , 8.3 ) • Drug Interactions: Review patient’s concomitant medications. Several drugs may significantly alter isavuconazole concentrations. Isavuconazole may alter concentrations of several drugs. ( 5.5 , 7 , 12.3 ) • Drug Particulates: Intravenous formulation may form insoluble particulates following reconstitution. Administer CRESEMBA through an in-line filter. ( 2.4 , 5.6 )

5.1Hepatic 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 .

5.2Infusion-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 .

5.3Hypersensitivity Reactions Anaphylactic Reactions Anaphylactic

reactions, with fatal outcome, have been reported during treatment with CRESEMBA. Symptoms including dyspnea, hypotension, generalized erythema with flushing, and urticaria have been reported in such cases often soon after the initiation of treatment. Severe Skin Reactions Severe skin reactions, such as Stevens-Johnson syndrome, have been reported during treatment with other azole antifungal agents. Discontinue CRESEMBA if a patient develops an anaphylactic or severe cutaneous adverse reaction and initiate supportive treatment as needed.

There is no information regarding cross-sensitivity between CRESEMBA and other azole antifungal agents though cross-sensitivity between other triazole agents has been reported. When prescribing CRESEMBA to patients with hypersensitivity to other azoles, monitor for signs and symptoms of hypersensitivity reactions.

5.4Embryo-Fetal Toxicity Based on

findings from animal reproduction studies, CRESEMBA may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Perinatal mortality was significantly increased in the offspring of pregnant rats dosed orally with isavuconazonium sulfate at 90 mg/kg/day (less than half the maintenance human dose based on AUC comparisons) during pregnancy through the weaning period.

Isavuconazonium chloride administration was associated with dose-related increases in the incidences of rudimentary cervical ribs in rats and rabbits at 30 and 45 mg/kg, respectively, doses equivalent to about 0.2 and 0.1 of the human maintenance dose based on AUC comparisons. In rats, dose-related increases in the incidences of zygomatic arch fusion and supernumerary ribs/rudimentary supernumerary ribs were also noted at 30 mg/kg and above, equivalent to one fifth the maintenance human dose based on AUC comparisons . Advise females of reproductive potential to use an effective method of contraception during treatment with CRESEMBA and for 28 days after the final dose .

5.5Drug Interactions Coadministration of

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

5.6Drug Particulates Following

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

4 CONTRAINDICATIONS • CRESEMBA is contraindicated in persons with known hypersensitivity to isavuconazole. • Coadministration 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 . • Coadministration of strong CYP3A4 inducers, such as rifampin, carbamazepine, St. John’s wort, or long acting barbiturates with CRESEMBA is contraindicated because strong CYP3A4 inducers can significantly decrease the plasma concentration of isavuconazole . • CRESEMBA shortened the QTc interval in a concentration-related manner. CRESEMBA is contraindicated in patients with familial short QT syndrome . • Hypersensitivity to CRESEMBA. • Coadministration with strong CYP3A4 inhibitors, such as ketoconazole or high-dose ritonavir. ( 4 , 7 ) • Coadministration with strong CYP3A4 inducers, such as rifampin, carbamazepine, St.

John’s wort, or long acting barbiturates. ( 4 , 7 ) • Use in patients with familial short QT syndrome.

8.1Pregnancy Risk Summary Based on

findings from animal studies, CRESEMBA may cause fetal harm when administered to a pregnant woman. There are no available human data on the use of CRESEMBA in pregnant women to evaluate for a 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 . Advise pregnant women of the potential risk to a fetus . The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a 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 2 to 4% and 15 to 20%, respectively.

Data Animal Data Isavuconazonium 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 6 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.

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 .

6.1Clinical 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.

6.2Post-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