Cresemba

CRESEMBA

Invasive aspergillosis (

• •
  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

• •
  CRESEMBA for injection
  is intended for use in patients who are 1 year of age and older (
  2.1 Important Administration Instructions for CRESEMBA

  CRESEMBA for Injection

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

  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
    [see Dosage and Administration].
  • •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.
  ,
  2.3 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 2below

  [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.

  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
  ).
• •
  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 Important Administration Instructions for CRESEMBA

  CRESEMBA for Injection

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

  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
    [see Dosage and Administration].
  • •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.
  ,
  2.6 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:

  • •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]
    .
  • •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.
  • •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]
    .
  • •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.
  ).
• •
  CRESEMBA for injection
  must be administered through an in-line filter over a minimum of 1 hour. (
  2.1 Important Administration Instructions for CRESEMBA

  CRESEMBA for Injection

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

  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
    [see Dosage and Administration].
  • •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.
  ,
  2.5 Dilution and Preparation Instructions for the Intravenous Administration of the CRESEMBA for Injection Formulation

  • •Based on the adult or pediatric dosage regimen
    [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.
  • •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.
  ).
• •
  CRESEMBA capsules
  are intended for use in patients who are 6 years of age and older and weighing 16 kg and greater (
  2.1 Important Administration Instructions for CRESEMBA

  CRESEMBA for Injection

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

  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
    [see Dosage and Administration].
  • •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.
  ,
  2.3 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 2below

  [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.

  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
  ).
• •
  CRESEMBA capsules
  can be taken with or without food. (
  2.1 Important Administration Instructions for CRESEMBA

  CRESEMBA for Injection

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

  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
    [see Dosage and Administration].
  • •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.
  ).
•  
   

• •The maximum of any individual loading or daily maintenance dose to be administered to any pediatric patient is 372 mg of CRESEMBA. (
  2.3 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 2below

  [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.

  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
  )

CRESEMBA 74.5 mg isavuconazonium sulfate (equivalent to 40 mg of isavuconazole) capsules are opaque and have a Swedish orange (reddish-brown) body imprinted with the Astellas logo in black ink and a Swedish orange cap imprinted with “557” in black ink.

CRESEMBA 186 mg isavuconazonium sulfate (equivalent to 100 mg of isavuconazole) capsules are opaque, elongated and have a Swedish orange (reddish-brown) body imprinted with the Astellas logo in black ink and a white cap imprinted with “766” 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.

• •Breastfeeding should be discontinued during treatment with CRESEMBA. (
  8.2 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.
  )
• •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 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: Serious hepatic reactions have been reported. Evaluate liver-related laboratory tests at the start and during the course of CRESEMBA therapy. (
  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.

  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 were reported during intravenous administration of CRESEMBA. Discontinue the infusion if these reactions occur. (
  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]

  .
  )
• •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. (
  5.3 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: 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 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]

  .
  ,
  8.1 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.
  ,
  8.3 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.
  )
• •Drug Interactions: Review patient’s concomitant medications. Several drugs may significantly alter isavuconazole concentrations. Isavuconazole may alter concentrations of several drugs. (
  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 and Drug 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 coadministered drugs on the pharmacokinetics of isavuconazole and the effect of isavuconazole on the pharmacokinetics of coadministered drugs

  [see Clinical Pharmacology]

  .

  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] .
  Lopinavir/ritonavir400 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] .
  Rifampin	Contraindicate coadministration of all potent CYP3A4 inducers	There is a 97% decrease in exposure of isavuconazole upon coadministration with rifampin [see Clinical Pharmacology] .

  Table 5. The Effect of CRESEMBA on the Pharmacokinetics of Other Drugs

  	Recommendation	Comments
  Lopinavir/ritonavir400 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] .
  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] .
  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] .
  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] .
  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] .
  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] .
  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] .
  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] .
  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] .
  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], which may increase the risk of vincristine-related adverse reactions.

  • •CYP3A4 inhibitors or inducers may alter the plasma concentrations of isavuconazole.
  • •Appropriate therapeutic drug monitoring and dose adjustment of immunosuppressants (i.e., tacrolimus, sirolimus, and cyclosporine) may be necessary when coadministered with CRESEMBA.
  • •Drugs with a narrow therapeutic window that are P-gp substrates, such as digoxin, may require dose adjustment when administered concomitantly with CRESEMBA.
  ,
  12.1 Mechanism of Action

  Isavuconazonium sulfate is the prodrug of isavuconazole, an azole antifungal

  [see Microbiology]

  .
  )
• •Drug Particulates: Intravenous formulation may form insoluble particulates following reconstitution. Administer CRESEMBA through an in-line filter. (
  2.4 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.

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