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CRESEMBA® Capsules Injection (isavuconazonium sulfate)
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use CRESEMBA safely and effectively. See full prescribing information for CRESEMBA.
CRESEMBA ® (isavuconazonium sulfate)
Capsules for oral administration
For Injection for intravenous administration
Initial U.S. Approval: 2015
INDICATIONS AND USAGE
CRESEMBA is an azole antifungal indicated for use in the treatment of:
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Invasive aspergillosis ( 1.1).
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Invasive mucormycosis ( 1.2).
DOSAGE AND ADMINISTRATION
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CRESEMBA for injection must be administered through an in-line filter over a minimum of 1 hour ( 2.1).
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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).
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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).
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Capsules can be taken with or without food ( 2.2).
DOSAGE FORMS AND STRENGTHS
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CRESEMBA capsules contain 186 mg of isavuconazonium sulfate (equivalent to 100 mg of isavuconazole) ( 3).
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CRESEMBA for injection is supplied in a single-dose vial as a sterile lyophilized powder containing 372 mg of isavuconazonium sulfate (equivalent to 200 mg of isavuconazole) ( 3).
CONTRAINDICATIONS
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Hypersensitivity to CRESEMBA ( 4).
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Coadministration with strong CYP3A4 inhibitors, such as ketoconazole or high-dose ritonavir ( 4, 7).
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Coadministration with strong CYP3A4 inducers, such as rifampin, carbamazepine, St. John’s wort, or long acting barbiturates ( 4, 7).
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Use in patients with familial short QT syndrome ( 4).
WARNINGS AND PRECAUTIONS
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Hepatic Adverse Drug Reactions: Serious hepatic reactions have been reported. eva luate liver-related laboratory tests at the start and during the course of CRESEMBA therapy ( 5.1).
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Infusion-related reactions were reported during intravenous administration of CRESEMBA. Discontinue the infusion if these reactions occur ( 5.2).
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Hypersensitivity Reactions: Serious hypersensitivity and severe skin reactions, such as anaphylaxis or Stevens Johnson syndrome, have been reported during treatment with other azole antifungal agents. Discontinue CRESEMBA for exfoliative cutaneous reactions ( 5.3).
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Embryo-Fetal Toxicity: Do not administer to pregnant women unless the benefit to the mother outweighs the risk to the fetus. Inform pregnant patients of the hazard ( 5.4).
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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).
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Drug Particulates: Intravenous formulation may form insoluble particulates following reconstitution. Administer CRESEMBA through an in-line filter ( 2.4, 5.6).
ADVERSE REACTIONS
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
DRUG INTERACTIONS
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CYP3A4 inhibitors or inducers may alter the plasma concentrations of isavuconazole ( 7).
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Appropriate therapeutic drug monitoring and dose adjustment of immunosuppressants (i.e., tacrolimus, sirolimus, and cyclosporine) may be necessary when co-administered with CRESEMBA ( 7).
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Drugs with a narrow therapeutic window that are P-gp substrates, such as digoxin, may require dose adjustment when administered concomitantly with CRESEMBA ( 7).
USE IN SPECIFIC POPULATIONS
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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).
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Mothers should not breast feed children while taking CRESEMBA ( 8.3).
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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).
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 3/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
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.
2 DOSAGE AND ADMINISTRATION
2.1 Important Instructions for Intravenous Administration
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Intravenous formulation must be administered via an infusion set with an in-line filter (pore size 0.2 to 1.2 micron).
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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.
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Do not infuse CRESEMBA with other intravenous medications.
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Flush intravenous lines with 0.9% sodium chloride injection, USP or 5% dextrose injection, USP prior to and after infusion of CRESEMBA.
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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.
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.
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Reconstitute one vial of CRESEMBA by adding 5 mL water for injection, USP to the vial.
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Gently shake to dissolve the powder completely.
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Visually inspect the reconstituted solution for particulate matter and discoloration. Reconstituted CRESEMBA should be clear and free of visible particulate.
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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
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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).
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Use gentle mixing or roll bag to minimize the formation of particulates. Avoid unnecessary vibration or vigorous shaking of the solution.
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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.
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Do not use a pneumatic transport system.
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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:
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0.9% sodium chloride injection, USP
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5% dextrose injection, USP
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 a Swedish orange (reddish-brown) body imprinted with the Astellas logo in black ink and a white cap imprinted with “ISA” 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 a single-dose vial as a sterile lyophilized white to yellow powder.
4 CONTRAINDICATIONS
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CRESEMBA is contraindicated in persons with known hypersensitivity to isavuconazole.
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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)].
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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)].
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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)].
5 WARNINGS AND PRECAUTIONS
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.
eva luate 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
Serious hypersensitivity and severe skin reactions, such as anaphylaxis or Stevens Johnson syndrome, have been reported during treatment with other azole antifungal agents. Discontinue CRESEMBA if a patient develops a severe cutaneous adverse reaction. There is no information regarding cross-sensitivity between CRESEMBA and other azole antifungal agents. Caution should be used when prescribing CRESEMBA to patients with hypersensitivity to other azoles.
5.4 Embryo-Fetal Toxicity
CRESEMBA may cause fetal harm when administered to a pregnant woman. CRESEMBA should be used during pregnancy only if the potential benefit to the patient outweighs the risk to the fetus. Women who become pregnant while receiving CRESEMBA are encouraged to contact their physician [see Use in Specific Populations (8.1)].
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)].
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. John’s 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)].
6 ADVERSE REACTIONS
The following are discussed in more detail in other sections of the labeling:
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Hepatic Adverse Drug Reactions [see Warnings and Precautions (5.1)]
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Infusion-Related Reactions [see Warnings and Precautions (5.2)]
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Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
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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.
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.
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