Cresemba Drug Information

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

• Isavuconazole is a sensitive substrate of CYP3A4. CYP3A4 inhibitors or inducers may alter the plasma concentrations of isavuconazole. Isavuconazole is a moderate inhibitor of CYP3A4, and a mild inhibitor of P-glycoprotein (P-gp), and organic cation transporter 2 (OCT2). Drug interaction studies were conducted to investigate the effect of coadministered drugs on the pharmacokinetics of isavuconazole and the effect of isavuconazole on the pharmacokinetics of coadministered drugs [see Clinical Pharmacology ( 12.3 )] . Table 4. Drug(s) Affecting Pharmacokinetics of CRESEMBA Recommendation Comments Ketoconazole Contraindicate coadministration of all potent CYP3A4 inhibitors There is more than a 5-fold increase in exposure of isavuconazole upon coadministration with ketoconazole [see Clinical Pharmacology ( 12.3 )] . Lopinavir/ritonavir 400 mg of lopinavir in combination with 100 mg of ritonavir. Caution is advised when CRESEMBA is coadministered with lopinavir/ritonavir There is a 96% increase in exposure of isavuconazole when coadministered with lopinavir/ritonavir [see Clinical Pharmacology ( 12.3 )] . Rifampin Contraindicate coadministration of all potent CYP3A4 inducers There is a 97% decrease in exposure of isavuconazole upon coadministration with rifampin [see Clinical Pharmacology ( 12.3 )] . Table 5. The Effect of CRESEMBA on the Pharmacokinetics of Other Drugs Recommendation Comments Lopinavir/ritonavir 400 mg of lopinavir in combination with 100 mg of ritonavir. Use with Caution Concomitant administration of lopinavir/ritonavir and CRESEMBA resulted in decreased exposure of lopinavir and ritonavir that could possibly result in loss of antiviral efficacy [see Clinical Pharmacology ( 12.3 )] . Atorvastatin Use with Caution Caution should be used when atorvastatin is used with CRESEMBA due to a potential increase in atorvastatin exposure. Monitor patients for adverse reactions that are typical of atorvastatin [see Clinical Pharmacology ( 12.3 )] . Cyclosporine Use with Caution Concomitant administration of CRESEMBA and cyclosporine results in increase in cyclosporine exposure. Monitor drug concentrations of cyclosporine and adjust dose as needed [see Clinical Pharmacology ( 12.3 )] . Sirolimus Use with Caution Concomitant administration of CRESEMBA and sirolimus results in increase in sirolimus exposure. Monitor drug concentrations of sirolimus and adjust dose as needed [see Clinical Pharmacology ( 12.3 )] . Tacrolimus Use with Caution Concomitant administration of CRESEMBA and tacrolimus results in increase in tacrolimus exposure. Monitor drug concentrations of tacrolimus and adjust dose as needed [see Clinical Pharmacology ( 12.3 )] . Midazolam Use with Caution Concomitant administration of CRESEMBA and midazolam results in increase in midazolam exposure. Consider dose reduction of midazolam when isavuconazole is coadministered [see Clinical Pharmacology ( 12.3 )] . Bupropion Use with Caution Concomitant administration of CRESEMBA and bupropion results in decrease in bupropion exposure. Dose increase of bupropion may be necessary when coadministered with CRESEMBA, but should not exceed the maximum recommended dose [see Clinical Pharmacology ( 12.3 )] . Mycophenolate Mofetil Use with Caution Concomitant administration of CRESEMBA and MMF results in increase in MMF exposure. Patients receiving CRESEMBA concurrently with MMF should be monitored for MPA-related toxicities [see Clinical Pharmacology ( 12.3 )] . Digoxin Use with Caution Concomitant administration of CRESEMBA and digoxin results in increase in digoxin exposure. Serum digoxin concentrations should be monitored and used for titration when dosed concurrently with CRESEMBA [see Clinical Pharmacology ( 12.3 )] . Vincristine Avoid Concomitant Use Avoid concomitant use with CRESEMBA in pediatric and adult patients. CRESEMBA is predicted to have a less than 2‑fold increase in vincristine exposure in pediatric and adult patients [see Clinical Pharmacology ( 12.3 )], which may increase the risk of vincristine-related adverse reactions.
• CYP3A4 inhibitors or inducers may alter the plasma concentrations of isavuconazole. ( 7 )
• Appropriate therapeutic drug monitoring and dose adjustment of immunosuppressants (i.e., tacrolimus, sirolimus, and cyclosporine) may be necessary when coadministered with CRESEMBA. ( 7 )
• Drugs with a narrow therapeutic window that are P-gp substrates, such as digoxin, may require dose adjustment when administered concomitantly with CRESEMBA. ( 7 )

Pregnancy 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 (see Data). 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.

Pediatric Use Invasive Aspergillosis The safety and effectiveness of CRESEMBA for injection for the treatment of invasive aspergillosis have been established in pediatric patients 1 year of age and older. The safety and effectiveness of CRESEMBA capsules for the treatment of invasive aspergillosis have been established in pediatric patients 6 year of age and older weighing 16 kg and greater. Use of CRESEMBA in this age group for treatment of invasive aspergillosis is supported by evidence from one adequate and well-controlled trial in adult patients and additional pharmacokinetic and safety data in pediatric patients 1 year of age and older.

Adverse reactions in this pediatric population were similar to those reported in the adult population. The safety and effectiveness of CRESEMBA capsules for treatment of invasive aspergillosis have not been established in pediatric patients younger than 6 years of age or who weigh less than 16 kg because the oral route of administration was not assessed in this pediatric patient age cohort. The safety and effectiveness of CRESEMBA for treatment of invasive aspergillosis in pediatric patients less than 1 year of age have not been established.

Invasive Mucormycosis The safety and effectiveness of CRESEMBA for injection for the treatment of invasive mucormycosis have been established in pediatric patients 1 year of age and older. The safety and effectiveness of CRESEMBA capsules for the treatment of invasive mucormycosis have been established in pediatric patients 6 year of age and older weighing 16 kg and greater. Use of CRESEMBA in this age group for treatment of invasive mucormycosis is supported by one open-label trial in adult patients with invasive mucormycosis, a retrospective review of survival data for adult patients with untreated invasive mucormycosis, and additional pharmacokinetic and safety data in pediatric patients 1 year of age and older . Adverse reactions in this pediatric population were similar to those reported in the adult population.

The safety and effectiveness of CRESEMBA capsules for treatment of invasive mucormycosis have not been established in pediatric patients younger than 6 years of age who weigh less than 16 kg because the oral route of administration was not assessed in this pediatric patient age cohort. The safety and effectiveness of CRESEMBA for treatment of invasive mucormycosis in pediatric patients less than 1 year of age have not been established.

• 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 [see Drug Interactions ( 7 ) and Clinical Pharmacology ( 12.3 )] .
• 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 [see Drug Interactions ( 7 ) and Clinical Pharmacology ( 12.3 )] .
• CRESEMBA shortened the QTc interval in a concentration-related manner. CRESEMBA is contraindicated in patients with familial short QT syndrome [see Clinical Pharmacology ( 12.2 )] .
• Hypersensitivity to CRESEMBA. ( 4 )
• 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. ( 4 )

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 a 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. Adverse reactions leading to discontinuation of study drug occurred in 7 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.