Data from FDA - Curated by EPG Health - Last updated 23 February 2017

Indication(s)

1 INDICATIONS AND USAGE CRESEMBA is an azole antifungal indicated for use in the treatment of: •Invasive aspergillosis (1.1). •Invasive mucormycosis (1.2). 1.1 Invasive Aspergillosis CRESEMBA 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.

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Advisory information

contraindications
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 [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).
Adverse reactions
6 ADVERSE REACTIONS 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)] 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. 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 A 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 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. Treatment-emergent adverse reactions resulting in permanent discontinuation were reported in 37 (14%) CRESEMBA-treated patients and 59 (23%) voriconazole-treated patients. Table 2 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 1 and Trial 2. Table 2. Selected Treatment-Emergent Adverse Reactions with Rates of 5% or Greater in CRESEMBA-treated Patients in Trial 1 a Elevated liver laboratory tests include reactions of increased alanine aminotransferase, aspartate aminotransferase, blood alkaline phosphatase, blood bilirubin, and gamma-glutamyltransferase. b Delirium includes adverse reactions of agitation, confusional state, delirium, disorientation, and mental status changes. System Organ Class Preferred Term 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 testsa 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) Deliriumb 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 2. This listing includes adverse reactions where a causal relationship to isavuconazole 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, paraesthesia, 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.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION •CRESEMBA for injection must be administered through an in-line filter over a minimum of 1 hour (2.1). •Loading Dose: 372 mg isavuconazonium sulfate (equivalent to 200 mg of isavuconazole) every 8 hours for 6 doses (48 hours) via oral (2 capsules) or intravenous administration (1 reconstituted vial) (2.2). •Maintenance 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). •Capsules can be taken with or without food (2.2). 2.1 Important Instructions for Intravenous Administration •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. 2.2 Dosage Regimen CRESEMBA (isavuconazonium sulfate) is the prodrug of isavuconazole, an azole antifungal drug. Prescribe CRESEMBA as shown in Table 1 below. Table 1. Dosage Regimen for CRESEMBA a 372 mg of isavuconazonium sulfate is equivalent to 200 mg of isavuconazole b 186 mg of isavuconazonium sulfate is equivalent to 100 mg of isavuconazole c Start maintenance doses 12 to 24 hours after the last loading dose Loading Dose Maintenance Dose c CRESEMBA for Injection 372 mga of isavuconazonium sulfate per vial 1 reconstituted vial (372 mga) intravenously every 8 hours for 6 doses (48 hours) 1 reconstituted vial (372 mga) intravenously once daily CRESEMBA Capsules 186 mgb of isavuconazonium sulfate per capsule 2 capsules (372 mga) orally every 8 hours for 6 doses (48 hours) 2 capsules (372 mga) orally once daily 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 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. •Reconstitute one vial of CRESEMBA by adding 5 mL water for injection, USP to the vial. •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 below 25°C for maximum 1 hour prior to preparation of the patient infusion solution. 2.4 Dilution and Preparation Instructions for the Injection Formulation •Remove 5 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). •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° to 8°C / 36° to 46°F) the infusion solution after dilution and complete the infusion within 24 hours. Do not freeze the infusion solution. 2.5 Compatibility for the Injection Formulation CRESEMBA for injection should only be administered with the following diluents: •0.9% sodium chloride injection, USP •5% dextrose injection, USP
Use in special populations
8 USE IN SPECIFIC POPULATIONS •Pregnancy: CRESEMBA should only be used if the benefits to the mother outweigh the risk to the fetus. Inform pregnant woman of risk (8.1). •Mothers should not breast feed children while taking CRESEMBA (8.3). •Use 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 Pregnancy Category C There are no adequate and well-controlled clinical studies of CRESEMBA in pregnant women. CRESEMBA should be used during pregnancy only if the potential benefit to the patient outweighs the risk to the fetus. Women who become pregnant during CRESEMBA treatment are encouraged to contact their physician. Risk Summary Based on animal data, CRESEMBA is predicted to have the potential for increasing the risk of adverse developmental outcomes above background risk. Animal Data 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 one fifth and one tenth of the clinical exposures 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 clinical dose based on AUC comparisons [see Nonclinical Toxicology (13.1)]. Skeletal abnormalities have also been observed in embryo-fetal development studies of other azole antifungal agents. 8.3 Nursing Mothers Isavuconazole is excreted in the milk of lactating rats following intravenous administration. Mothers should not breast feed while taking CRESEMBA. 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 2 and 3 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 3 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 A 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)].
Pregnancy and lactation
8.3 Nursing Mothers Isavuconazole is excreted in the milk of lactating rats following intravenous administration. Mothers should not breast feed while taking CRESEMBA.

Interactions

7 DRUG INTERACTIONS 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 co-administered drugs on pharmacokinetics of isavuconazole and the effect of isavuconazole on the pharmacokinetics of co-administered drugs [see Clinical Pharmacology (12.3)]. Table 3. Drug(s) Affecting Pharmacokinetics of CRESEMBA a 400 mg of lopinavir in combination with 100 mg of ritonavir. 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/ritonavira 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 4. The Effect of CRESEMBA on the Pharmacokinetics of Other Drugs a 400 mg of lopinavir in combination with 100 mg of ritonavir. Recommendation Comments Lopinavir/ritonavira 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. 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)]. •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 co-administered 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).

More information

Category Value
Authorisation number NDA207500
Orphan designation No
Product NDC 0469-0320,0469-0420,0469-0520
Date Last Revised 05-08-2016
Type HUMAN PRESCRIPTION DRUG
RXCUI 1608333
Marketing authorisation holder Astellas Pharma US, Inc.