Cresemba

Invasive 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 [see Clinical Studies  and Clinical Pharmacology ]

CRESEMBA capsules: adults and pediatric patients 6 years of age and older who weigh 16 kilograms (kg) and greater [see Dosage and Administration  Clinical Studies ( 14.1) and Clinical Pharmacology ]

Invasive 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 [see Clinical Studies and Clinical Pharmacology ]

CRESEMBA capsules: adults and pediatric patients 6 years of age and older who weigh 16 kg and greater [see Dosage and Administration ], Clinical Studies and Clinical Pharmacology ]

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.

Important Administration Instructions for CRESEMBA

CRESEMBA for Injection

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CRESEMBA for injection is intended for use in patients who are 1 year of age and older [see Dosage and 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.

Nasogastric Tube Administration of CRESEMBA for Injection

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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 [see Dosage and Administration ].

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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.

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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.

Recommended 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.

Recommended 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 [see Clinical Pharmacology ( 12.3)]. The maximum of any individual loading or daily maintenance dose to be administered to any pediatric patient is 372 mg of CRESEMBA.

Reconstitution 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.

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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.

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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 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 [see Dosage and Administration ].

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For nasogastric tube administration, the reconstituted solution should be administered within 1 hour of reconstitution [see Dosage and Administration ], 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 [see Dosage and Administration ( 2.7)]. 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.

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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°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.

 Preparation Instructions for the Nasogastric Tube Administration of the CRESEMBA for Injection Formulation

CRESEMBA for injection can be administered through a nasogastric tube as follows:

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Utilizing aseptic technique, reconstitute one vial of CRESEMBA for injection (equivalent to 200 mg isavuconazole) with 5 mL of water for injection, USP [see Dosage and Administration ].

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Based on the adult or pediatric (6 years of age to less than 18 years of age) CRESEMBA for injection dosage regimen [see Dosage and Administration ], 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.

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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 [see Clinical Pharmacology ].

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Administer the reconstituted solution via the nasogastric tube within 1 hour of reconstitution. Discard any unused portion of the reconstituted solution.

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Do not administer CRESEMBA capsules through a nasogastric tube.

 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

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 [see Warnings and Precautions ].

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.

Lactation

Risk Summary

There are no data on the presence of isavuconazole in human milk, the effects on the breastfed infant or the effects on milk production. Isavuconazole was present in the milk of lactating rats following intravenous administration. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Therefore, breastfeeding should be discontinued during treatment with CRESEMBA.

Females and Males of Reproductive Potential

Contraception

CRESEMBA may cause embryo-fetal harm when administered to pregnant women [see Warnings and Precautions and Use in Specific Populations ]. Advise female patients of reproductive potential to use effective contraception during treatment with CRESEMBA and for 28 days after the final 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 [see Clinical Pharmacology ( 12.3)]. Adverse reactions in this pediatric population were similar to those reported in the adult population [see Adverse Reactions ]. 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 [see Clinical Pharmacology ]. Adverse reactions in this pediatric population were similar to those reported in the adult population [see Adverse Reactions ]. 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.

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 ]. No dose adjustment of CRESEMBA is needed in elderly patients.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

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 ].

Hepatic Impairment

No dose adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh Class A and B) [see Clinical Pharmacology ]. 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 ].

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.

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 [see Adverse Reactions ].

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 ].

Hypersensitivity 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.

Embryo-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 [see Use in Specific Populations ].

Advise females of reproductive potential to use an effective method of contraception during treatment with CRESEMBA and for 28 days after the final dose [see Use in Specific Populations ].

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 and Drug Interactions ].

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 ].