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

12.3 Pharmacokinetics

General Pharmacokinetics

In healthy subjects, the pharmacokinetics of isavuconazole following oral administration of CRESEMBA capsules at isavuconazole equivalent doses up to 600 mg per day (6 capsules) are dose proportional (Table 6). Based on a population pharmacokinetics analysis of healthy subjects and patients, the mean plasma half-life of isavuconazole was 130 hours and the mean volume of distribution (V_ss) was approximately 450 L following intravenous administration.

Table 6. Steady State Pharmacokinetic Parameters of Isavuconazole Following Administration of 186 mg CRESEMBA Capsules
Parameter	CRESEMBA 186 mg 2 Capsules Each capsule contains the equivalent of 100 mg of isavuconazole. (n = 37)	CRESEMBA 186 mg 6 Capsules (n = 32)
C_max(mg/L)
Mean SD CV %	7.5 1.9 25.2	20.0 3.6 17.9
t_max(hr)
Median Range	3.0 2.0 – 4.0	4.0 2.0 – 4.0
AUC (mg•hr/L)
Mean SD CV %	121.4 35.8 29.5	352.8 72.0 20.4

Following oral administration of CRESEMBA capsules at an isavuconazole equivalent dose of 200 mg in 66 fasted healthy male subjects, a single dose administration of two 186 mg CRESEMBA capsules and five 74.5 mg CRESEMBA capsules exhibited a mean (SD) C_maxand AUC of 3.3 (0.6) mg/L and 112.2 (30.3) mg·hr/L, respectively, and 3.3 (0.6) mg/L and 118.0 (33.1) mg·hr/L, respectively.

Absorption

After oral administration of CRESEMBA in healthy volunteers, the active moiety, isavuconazole, generally reaches maximum plasma concentrations (C_max) 2 hours to 3 hours after single and multiple dosing. The absolute bioavailability of isavuconazole following oral administration of CRESEMBA is 98%. No significant concentrations of the prodrug or inactive cleavage product were seen in plasma after oral administration.

Following intravenous administration of CRESEMBA, maximal plasma concentrations of the prodrug and inactive cleavage product were detectable during infusion and declined rapidly following the end of administration. The prodrug was below the level of detection by 1.25 hours after the start of a one-hour infusion. The total exposure of the prodrug based on AUC was less than 1% that of isavuconazole. The inactive cleavage product was quantifiable in some subjects up to 8 hours after the start of infusion. The total exposure of inactive cleavage product based on AUC was approximately 1.3% that of isavuconazole.

CRESEMBA given orally as an intravenous solution administered via nasogastric (NG) tube provides systemic isavuconazole exposure that is similar to the oral capsule (Table 7).

Table 7. Statistical Comparison of Plasma Pharmacokinetics of Isavuconazole Following Single Oral Dose Administration of 2 Capsules of 186 mg (Equivalent to 200 mg Isavuconazole) and Single Intravenous Solution Dose Administration of 372 mg (Equivalent to 200 mg Isavuconazole) via Nasogastric (NG) Tube in Healthy Adult Subjects Under Fasted Conditions
	CRESEMBA IV Solution via NG Tube		CRESEMBA Oral Capsules		NG Tube/Oral Capsule
Pharmacokinetic Parameter	N	Mean (%CV)	N	Mean (%CV)	GMR (90% CI)
C_max(mg/L)	13	2.3 (23.6)	13	2.2 (26.7)	105.34 (89-124)
AUC_0-72hr (mg·hr/L)	13	34.9 (22.1)	13	35.8 (24.6)	97.81 (93-103)
AUC_0-∞ (mg·hr/L)	12	98.1 (44.5)	12	100.1 (46.8)	99.27 (93-106)
GMR = Geometric least-squares mean ratio; CI = confidence interval

Effect of Food

Coadministration of CRESEMBA equivalent to isavuconazole 400 mg oral dose with a high-fat meal reduced isavuconazole C_maxby 9% and increased AUC by 9%. CRESEMBA can be taken with or without food.

Distribution

Isavuconazole is extensively distributed with a mean steady state volume of distribution (V_ss) of approximately 450 L. Isavuconazole is highly protein bound (greater than 99%), predominantly to albumin.

Elimination

Metabolism

in vitro

studies isavuconazonium sulfate is rapidly hydrolyzed in blood to isavuconazole by esterases, predominantly by butylcholinesterase. Isavuconazole is a substrate of cytochrome P450 enzymes 3A4 and 3A5.

Following single doses of [cyano¹⁴C] isavuconazonium and [pyridinylmethyl¹⁴C] isavuconazonium in humans, in addition to the active moiety (isavuconazole) and the inactive cleavage product, a number of minor metabolites were identified. Except for the active moiety isavuconazole, no individual metabolite was observed with an AUC greater than 10% of drug-related material.

In vivo

studies indicate that CYP3A4, CYP3A5 and subsequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole.

Excretion

Following oral administration of radio-labeled isavuconazonium sulfate to healthy volunteers, a mean of 46.1% of the total radioactive dose was recovered in the feces and 45.5% was recovered in the urine.

Renal excretion of isavuconazole itself was less than 1% of the dose administered.

The inactive cleavage product is primarily eliminated by metabolism and subsequent renal excretion of the metabolites. Renal elimination of intact cleavage product was less than 1% of the total dose administered. Following intravenous administration of radio-labeled cleavage product, 95% of the total radioactive dose was excreted in the urine.

Special populations

Geriatric Patients

The AUC of isavuconazole following a single oral dose of CRESEMBA equivalent to 200 mg isavuconazole in elderly subjects (65 years and older) was similar to that in younger volunteers (18 years to 45 years). The AUC was similar between younger female and male subjects and between elderly and younger males.

Elderly female AUC estimates were 38% and 47% greater than AUC estimates obtained in elderly males and younger females, respectively. The pharmacokinetic difference in elderly females receiving CRESEMBA are not considered to be clinically significant. Therefore, no dose adjustment is required based on age and gender.

Pediatric Patients

The pharmacokinetics of isavuconazole were evaluated in two clinical studies (N = 73) in pediatric patients aged 1 to less than 18 years of age which included twenty-eight patients with at least possible invasive aspergillosis or possible invasive mucormycosis.

Table 8. Derived Steady State Isavuconazole AUC (mg•hr/L) values in Pediatric Patients, by Age Group
Dosage	15 mg/kg Estimated AUCss values of 15 mg/kg that were derived from existing values of pediatric patients that received 10 mg/kg of CRESEMBA for injection administered intravenously.	10 mg/kg CRESEMBA for injection administered intravenously.	10 mg/kg or Maximum Dose of 372 mg CRESEMBA for injection administered intravenously or CRESEMBA capsules administered orally.
Age Group	1 to < 3 years (n=5)	3 to < 6 years (n=10)	6 to < 12 years (n=29)	12 to < 18 years (n=29)
Mean	80.2	103.3	97.3	104.2
Median	64.3	110.3	87.7	97.7
Minimum - Maximum	53.7 - 155	51.5 – 159.1	37.8– 153.8	35.5 – 215.6

Race

A 2-compartment population pharmacokinetic model was developed to assess the pharmacokinetics of isavuconazole between healthy Western and Chinese subjects. Chinese subjects were found to have on average a 40% lower clearance compared to Western subjects (1.6 L/hr for Chinese subjects as compared to 2.6 L/hr for Western subjects) and therefore approximately 50% higher AUC than Western subjects. Body mass index (BMI) did not play a role in the observed differences. No dose adjustment is recommended for Chinese patients.

Gender

AUC estimates were similar between young female and male subjects (18 years to 45 years). There was a difference in AUC for elderly females

(see

Geriatric

section above)

. No dose adjustment is required based on gender.

Patients with Renal Impairment

Total isavuconazole AUC and C_maxwere not affected to a clinically meaningful extent in subjects with mild, moderate and severe renal impairment relative to healthy controls. No dose adjustment is necessary in patients with renal impairment.

Isavuconazole is not readily dialyzable. A dose adjustment is not warranted in patients with ESRD.

Patients with Hepatic Impairment

After a single-dose of CRESEMBA equivalent to 100 mg of isavuconazole was administered to 32 patients with mild (Child-Pugh Class A) hepatic impairment and 32 patients with moderate (Child-Pugh Class B) hepatic impairment (16 intravenous and 16 oral patients per Child-Pugh Class), the least squares mean systemic exposure (AUC) increased 64% and 84% in the Child-Pugh Class A group and the Child-Pugh Class B group, respectively, relative to 32 age and weight-matched healthy subjects with normal hepatic function. Mean C_maxwas 2% lower in the Child-Pugh Class A group and 30% lower in the Child-Pugh Class B group. The population pharmacokinetic evaluation of isavuconazole in healthy subjects and patients with mild and moderate hepatic impairment demonstrated that the mild and moderate hepatic impairment population had 40% and 48% lower isavuconazole clearance (CL) values, respectively, compared to the healthy population. It is recommended that the standard CRESEMBA loading dose and maintenance dose regimen be utilized in patients with mild to moderate hepatic disease. CRESEMBA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).

Drug Interaction Studies

In Vitro Studies

CYP450 Enzymes:

Isavuconazole is a substrate of CYP3A4 and CYP3A5. Isavuconazole is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Isavuconazole is an inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9.

Transporter Systems:

Isavuconazole is an inhibitor of P-gp-, BCRP- and OCT2.

Clinical Studies and Model-Informed Approaches

The effect of coadministration of drugs on the pharmacokinetics of isavuconazole and the effect of isavuconazole on the pharmacokinetics of coadministered drugs were studied after single and multiple doses of isavuconazole in healthy subjects.

The effects of ketoconazole, rifampin, lopinavir/ritonavir, and esomeprazole on isavuconazole are shown inFigure 1.

Ketoconazole:

As a strong CYP3A4 inhibitor, ketoconazole increased the isavuconazole C_maxby 9% and isavuconazole AUC by 422% after multiple-dose administration of ketoconazole (200 mg twice daily) for 24 days and a single-dose of CRESEMBA equivalent to 200 mg of isavuconazole. Isavuconazole is a sensitive CYP3A4 substrate and use with strong CYP3A4 inhibitors are contraindicated perSection 4andFigure 1.

Lopinavir/Ritonavir:

Lopinavir/ritonavir (400 mg/100 mg twice daily) increased the C_maxand AUC of isavuconazole by 74% and 96%, respectively, with concurrent decreases in the mean AUCs of lopinavir and ritonavir by 27% and 31%, respectively.

Rifampin:

Rifampin (600 mg) decreased the mean C_maxand AUC of isavuconazole by 75% and 97%, respectively, when coadministered with multiple doses of CRESEMBA and thus, coadministration of CRESEMBA with strong CYP3A4 inducers is contraindicated.

Figure 1. The Effect of Coadministered Drugs on Isavuconazole Exposure

The effects of isavuconazole on ritonavir, lopinavir, prednisone, combined oral contraceptives (ethinyl estradiol and norethindrone), cyclosporine, atorvastatin, sirolimus, midazolam, and tacrolimus are shown inFigure 2.

CYP3A4 Substrates:

CRESEMBA increased the systemic exposure of sensitive CYP3A4 substrates midazolam, sirolimus and tacrolimus approximately 2-fold, and therefore CRESEMBA is a moderate inhibitor of CYP3A4.

Figure 2. The Effect of Isavuconazole on Coadministered CYP3A4 Substrate Medications

The effects of isavuconazole on other CYP substrates: caffeine, bupropion, methadone, repaglinide, warfarin, omeprazole, and dextromethorphan, are shown inFigure 3.

Figure 3. The Effect of Isavuconazole on Exposure of Coadministered CYP Substrate Medications

The effects of isavuconazole on the substrates of UGT and transporters: mycophenolate mofetil (MMF), methotrexate, metformin, and digoxin are shown inFigure 4.

Figure 4. The Effect of Isavuconazole on Exposure on the Substrates of UGT and Transporters

Vincristine:

Vincristine (P-gp substrate) exposure is predicted to increase by less than 2-fold in pediatric and adult patients following concomitant administration with CRESEMBA.

Figure 1. The Effect of Co-administered Drugs on Isavuconazole Exposure

Figure 2. The Effect of Isavuconazole on Co-administered CYP3A4 Substrate Medications

Figure 3. The Effect of Isavuconazole on Exposure of Co-administered CYP Substrate Medications

Figure 4. The Effect of Isavuconazole on Exposure on the Substrates of UGT and Transporters

(

12.3 Pharmacokinetics

General Pharmacokinetics

Table 6. Steady State Pharmacokinetic Parameters of Isavuconazole Following Administration of 186 mg CRESEMBA Capsules
Parameter	CRESEMBA 186 mg 2 Capsules Each capsule contains the equivalent of 100 mg of isavuconazole. (n = 37)	CRESEMBA 186 mg 6 Capsules (n = 32)
C_max(mg/L)
Mean SD CV %	7.5 1.9 25.2	20.0 3.6 17.9
t_max(hr)
Median Range	3.0 2.0 – 4.0	4.0 2.0 – 4.0
AUC (mg•hr/L)
Mean SD CV %	121.4 35.8 29.5	352.8 72.0 20.4

Absorption

CRESEMBA given orally as an intravenous solution administered via nasogastric (NG) tube provides systemic isavuconazole exposure that is similar to the oral capsule (Table 7).

Table 7. Statistical Comparison of Plasma Pharmacokinetics of Isavuconazole Following Single Oral Dose Administration of 2 Capsules of 186 mg (Equivalent to 200 mg Isavuconazole) and Single Intravenous Solution Dose Administration of 372 mg (Equivalent to 200 mg Isavuconazole) via Nasogastric (NG) Tube in Healthy Adult Subjects Under Fasted Conditions
	CRESEMBA IV Solution via NG Tube		CRESEMBA Oral Capsules		NG Tube/Oral Capsule
Pharmacokinetic Parameter	N	Mean (%CV)	N	Mean (%CV)	GMR (90% CI)
C_max(mg/L)	13	2.3 (23.6)	13	2.2 (26.7)	105.34 (89-124)
AUC_0-72hr (mg·hr/L)	13	34.9 (22.1)	13	35.8 (24.6)	97.81 (93-103)
AUC_0-∞ (mg·hr/L)	12	98.1 (44.5)	12	100.1 (46.8)	99.27 (93-106)
GMR = Geometric least-squares mean ratio; CI = confidence interval

Effect of Food

Coadministration of CRESEMBA equivalent to isavuconazole 400 mg oral dose with a high-fat meal reduced isavuconazole C_maxby 9% and increased AUC by 9%. CRESEMBA can be taken with or without food.

Distribution

Elimination

Metabolism

in vitro

In vivo

studies indicate that CYP3A4, CYP3A5 and subsequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole.

Excretion

Renal excretion of isavuconazole itself was less than 1% of the dose administered.

Special populations

Geriatric Patients

Pediatric Patients

Table 8. Derived Steady State Isavuconazole AUC (mg•hr/L) values in Pediatric Patients, by Age Group
Dosage	15 mg/kg Estimated AUCss values of 15 mg/kg that were derived from existing values of pediatric patients that received 10 mg/kg of CRESEMBA for injection administered intravenously.	10 mg/kg CRESEMBA for injection administered intravenously.	10 mg/kg or Maximum Dose of 372 mg CRESEMBA for injection administered intravenously or CRESEMBA capsules administered orally.
Age Group	1 to < 3 years (n=5)	3 to < 6 years (n=10)	6 to < 12 years (n=29)	12 to < 18 years (n=29)
Mean	80.2	103.3	97.3	104.2
Median	64.3	110.3	87.7	97.7
Minimum - Maximum	53.7 - 155	51.5 – 159.1	37.8– 153.8	35.5 – 215.6

Race

Gender

AUC estimates were similar between young female and male subjects (18 years to 45 years). There was a difference in AUC for elderly females

(see

Geriatric

section above)

. No dose adjustment is required based on gender.

Patients with Renal Impairment

Isavuconazole is not readily dialyzable. A dose adjustment is not warranted in patients with ESRD.

Patients with Hepatic Impairment

Drug Interaction Studies

In Vitro Studies

CYP450 Enzymes:

Isavuconazole is a substrate of CYP3A4 and CYP3A5. Isavuconazole is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Isavuconazole is an inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9.

Transporter Systems:

Isavuconazole is an inhibitor of P-gp-, BCRP- and OCT2.

Clinical Studies and Model-Informed Approaches

The effects of ketoconazole, rifampin, lopinavir/ritonavir, and esomeprazole on isavuconazole are shown inFigure 1.

Ketoconazole:

Lopinavir/Ritonavir:

Rifampin:

Figure 1. The Effect of Coadministered Drugs on Isavuconazole Exposure

CYP3A4 Substrates:

CRESEMBA increased the systemic exposure of sensitive CYP3A4 substrates midazolam, sirolimus and tacrolimus approximately 2-fold, and therefore CRESEMBA is a moderate inhibitor of CYP3A4.

Figure 2. The Effect of Isavuconazole on Coadministered CYP3A4 Substrate Medications

The effects of isavuconazole on other CYP substrates: caffeine, bupropion, methadone, repaglinide, warfarin, omeprazole, and dextromethorphan, are shown inFigure 3.

Figure 3. The Effect of Isavuconazole on Exposure of Coadministered CYP Substrate Medications

The effects of isavuconazole on the substrates of UGT and transporters: mycophenolate mofetil (MMF), methotrexate, metformin, and digoxin are shown inFigure 4.

Figure 4. The Effect of Isavuconazole on Exposure on the Substrates of UGT and Transporters

Vincristine:

Vincristine (P-gp substrate) exposure is predicted to increase by less than 2-fold in pediatric and adult patients following concomitant administration with CRESEMBA.

)]

CYP3A4 Substrates:

CRESEMBA increased the systemic exposure of sensitive CYP3A4 substrates midazolam, sirolimus and tacrolimus approximately 2-fold, and therefore CRESEMBA is a moderate inhibitor of CYP3A4.

The effects of isavuconazole on other CYP substrates: caffeine, bupropion, methadone, repaglinide, warfarin, omeprazole, and dextromethorphan, are shown inFigure 3.

The effects of isavuconazole on the substrates of UGT and transporters: mycophenolate mofetil (MMF), methotrexate, metformin, and digoxin are shown inFigure 4.

Vincristine:

Vincristine (P-gp substrate) exposure is predicted to increase by less than 2-fold in pediatric and adult patients following concomitant administration with CRESEMBA.

(

12.3 Pharmacokinetics

General Pharmacokinetics

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

12.3 Pharmacokinetics

General Pharmacokinetics

Table 6. Steady State Pharmacokinetic Parameters of Isavuconazole Following Administration of 186 mg CRESEMBA Capsules
Parameter	CRESEMBA 186 mg 2 Capsules Each capsule contains the equivalent of 100 mg of isavuconazole. (n = 37)	CRESEMBA 186 mg 6 Capsules (n = 32)
C_max(mg/L)
Mean SD CV %	7.5 1.9 25.2	20.0 3.6 17.9
t_max(hr)
Median Range	3.0 2.0 – 4.0	4.0 2.0 – 4.0
AUC (mg•hr/L)
Mean SD CV %	121.4 35.8 29.5	352.8 72.0 20.4

Absorption

CRESEMBA given orally as an intravenous solution administered via nasogastric (NG) tube provides systemic isavuconazole exposure that is similar to the oral capsule (Table 7).

Table 7. Statistical Comparison of Plasma Pharmacokinetics of Isavuconazole Following Single Oral Dose Administration of 2 Capsules of 186 mg (Equivalent to 200 mg Isavuconazole) and Single Intravenous Solution Dose Administration of 372 mg (Equivalent to 200 mg Isavuconazole) via Nasogastric (NG) Tube in Healthy Adult Subjects Under Fasted Conditions
	CRESEMBA IV Solution via NG Tube		CRESEMBA Oral Capsules		NG Tube/Oral Capsule
Pharmacokinetic Parameter	N	Mean (%CV)	N	Mean (%CV)	GMR (90% CI)
C_max(mg/L)	13	2.3 (23.6)	13	2.2 (26.7)	105.34 (89-124)
AUC_0-72hr (mg·hr/L)	13	34.9 (22.1)	13	35.8 (24.6)	97.81 (93-103)
AUC_0-∞ (mg·hr/L)	12	98.1 (44.5)	12	100.1 (46.8)	99.27 (93-106)
GMR = Geometric least-squares mean ratio; CI = confidence interval

Effect of Food

Coadministration of CRESEMBA equivalent to isavuconazole 400 mg oral dose with a high-fat meal reduced isavuconazole C_maxby 9% and increased AUC by 9%. CRESEMBA can be taken with or without food.

Distribution

Elimination

Metabolism

in vitro

In vivo

studies indicate that CYP3A4, CYP3A5 and subsequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole.

Excretion

Renal excretion of isavuconazole itself was less than 1% of the dose administered.

Special populations

Geriatric Patients

Pediatric Patients

Table 8. Derived Steady State Isavuconazole AUC (mg•hr/L) values in Pediatric Patients, by Age Group
Dosage	15 mg/kg Estimated AUCss values of 15 mg/kg that were derived from existing values of pediatric patients that received 10 mg/kg of CRESEMBA for injection administered intravenously.	10 mg/kg CRESEMBA for injection administered intravenously.	10 mg/kg or Maximum Dose of 372 mg CRESEMBA for injection administered intravenously or CRESEMBA capsules administered orally.
Age Group	1 to < 3 years (n=5)	3 to < 6 years (n=10)	6 to < 12 years (n=29)	12 to < 18 years (n=29)
Mean	80.2	103.3	97.3	104.2
Median	64.3	110.3	87.7	97.7
Minimum - Maximum	53.7 - 155	51.5 – 159.1	37.8– 153.8	35.5 – 215.6

Race

Gender

AUC estimates were similar between young female and male subjects (18 years to 45 years). There was a difference in AUC for elderly females

(see

Geriatric

section above)

. No dose adjustment is required based on gender.

Patients with Renal Impairment

Isavuconazole is not readily dialyzable. A dose adjustment is not warranted in patients with ESRD.

Patients with Hepatic Impairment

Drug Interaction Studies

In Vitro Studies

CYP450 Enzymes:

Isavuconazole is a substrate of CYP3A4 and CYP3A5. Isavuconazole is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Isavuconazole is an inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9.

Transporter Systems:

Isavuconazole is an inhibitor of P-gp-, BCRP- and OCT2.

Clinical Studies and Model-Informed Approaches

The effects of ketoconazole, rifampin, lopinavir/ritonavir, and esomeprazole on isavuconazole are shown inFigure 1.

Ketoconazole:

Lopinavir/Ritonavir:

Rifampin:

Table 6. Steady State Pharmacokinetic Parameters of Isavuconazole Following Administration of 186 mg CRESEMBA Capsules
Parameter	CRESEMBA 186 mg 2 Capsules Each capsule contains the equivalent of 100 mg of isavuconazole. (n = 37)	CRESEMBA 186 mg 6 Capsules (n = 32)
C_max(mg/L)
Mean SD CV %	7.5 1.9 25.2	20.0 3.6 17.9
t_max(hr)
Median Range	3.0 2.0 – 4.0	4.0 2.0 – 4.0
AUC (mg•hr/L)
Mean SD CV %	121.4 35.8 29.5	352.8 72.0 20.4

Absorption

CRESEMBA given orally as an intravenous solution administered via nasogastric (NG) tube provides systemic isavuconazole exposure that is similar to the oral capsule (Table 7).

Table 7. Statistical Comparison of Plasma Pharmacokinetics of Isavuconazole Following Single Oral Dose Administration of 2 Capsules of 186 mg (Equivalent to 200 mg Isavuconazole) and Single Intravenous Solution Dose Administration of 372 mg (Equivalent to 200 mg Isavuconazole) via Nasogastric (NG) Tube in Healthy Adult Subjects Under Fasted Conditions
	CRESEMBA IV Solution via NG Tube		CRESEMBA Oral Capsules		NG Tube/Oral Capsule
Pharmacokinetic Parameter	N	Mean (%CV)	N	Mean (%CV)	GMR (90% CI)
C_max(mg/L)	13	2.3 (23.6)	13	2.2 (26.7)	105.34 (89-124)
AUC_0-72hr (mg·hr/L)	13	34.9 (22.1)	13	35.8 (24.6)	97.81 (93-103)
AUC_0-∞ (mg·hr/L)	12	98.1 (44.5)	12	100.1 (46.8)	99.27 (93-106)
GMR = Geometric least-squares mean ratio; CI = confidence interval

Effect of Food

Coadministration of CRESEMBA equivalent to isavuconazole 400 mg oral dose with a high-fat meal reduced isavuconazole C_maxby 9% and increased AUC by 9%. CRESEMBA can be taken with or without food.

Distribution

Elimination

Metabolism

in vitro

In vivo

studies indicate that CYP3A4, CYP3A5 and subsequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole.

Excretion

Renal excretion of isavuconazole itself was less than 1% of the dose administered.

Special populations

Geriatric Patients

Pediatric Patients

Table 8. Derived Steady State Isavuconazole AUC (mg•hr/L) values in Pediatric Patients, by Age Group
Dosage	15 mg/kg Estimated AUCss values of 15 mg/kg that were derived from existing values of pediatric patients that received 10 mg/kg of CRESEMBA for injection administered intravenously.	10 mg/kg CRESEMBA for injection administered intravenously.	10 mg/kg or Maximum Dose of 372 mg CRESEMBA for injection administered intravenously or CRESEMBA capsules administered orally.
Age Group	1 to < 3 years (n=5)	3 to < 6 years (n=10)	6 to < 12 years (n=29)	12 to < 18 years (n=29)
Mean	80.2	103.3	97.3	104.2
Median	64.3	110.3	87.7	97.7
Minimum - Maximum	53.7 - 155	51.5 – 159.1	37.8– 153.8	35.5 – 215.6

Race

Gender

AUC estimates were similar between young female and male subjects (18 years to 45 years). There was a difference in AUC for elderly females

(see

Geriatric

section above)

. No dose adjustment is required based on gender.

Patients with Renal Impairment

Isavuconazole is not readily dialyzable. A dose adjustment is not warranted in patients with ESRD.

Patients with Hepatic Impairment

Drug Interaction Studies

In Vitro Studies

CYP450 Enzymes:

Isavuconazole is a substrate of CYP3A4 and CYP3A5. Isavuconazole is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Isavuconazole is an inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9.

Transporter Systems:

Isavuconazole is an inhibitor of P-gp-, BCRP- and OCT2.

Clinical Studies and Model-Informed Approaches

The effects of ketoconazole, rifampin, lopinavir/ritonavir, and esomeprazole on isavuconazole are shown inFigure 1.

Ketoconazole:

Lopinavir/Ritonavir:

Rifampin:

Figure 1. The Effect of Coadministered Drugs on Isavuconazole Exposure

CYP3A4 Substrates:

CRESEMBA increased the systemic exposure of sensitive CYP3A4 substrates midazolam, sirolimus and tacrolimus approximately 2-fold, and therefore CRESEMBA is a moderate inhibitor of CYP3A4.

Figure 2. The Effect of Isavuconazole on Coadministered CYP3A4 Substrate Medications

The effects of isavuconazole on other CYP substrates: caffeine, bupropion, methadone, repaglinide, warfarin, omeprazole, and dextromethorphan, are shown inFigure 3.

Figure 3. The Effect of Isavuconazole on Exposure of Coadministered CYP Substrate Medications

The effects of isavuconazole on the substrates of UGT and transporters: mycophenolate mofetil (MMF), methotrexate, metformin, and digoxin are shown inFigure 4.

Figure 4. The Effect of Isavuconazole on Exposure on the Substrates of UGT and Transporters

Vincristine:

Vincristine (P-gp substrate) exposure is predicted to increase by less than 2-fold in pediatric and adult patients following concomitant administration with CRESEMBA.

)].

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

12.3 Pharmacokinetics

General Pharmacokinetics

Table 6. Steady State Pharmacokinetic Parameters of Isavuconazole Following Administration of 186 mg CRESEMBA Capsules
Parameter	CRESEMBA 186 mg 2 Capsules Each capsule contains the equivalent of 100 mg of isavuconazole. (n = 37)	CRESEMBA 186 mg 6 Capsules (n = 32)
C_max(mg/L)
Mean SD CV %	7.5 1.9 25.2	20.0 3.6 17.9
t_max(hr)
Median Range	3.0 2.0 – 4.0	4.0 2.0 – 4.0
AUC (mg•hr/L)
Mean SD CV %	121.4 35.8 29.5	352.8 72.0 20.4

Absorption

CRESEMBA given orally as an intravenous solution administered via nasogastric (NG) tube provides systemic isavuconazole exposure that is similar to the oral capsule (Table 7).

Table 7. Statistical Comparison of Plasma Pharmacokinetics of Isavuconazole Following Single Oral Dose Administration of 2 Capsules of 186 mg (Equivalent to 200 mg Isavuconazole) and Single Intravenous Solution Dose Administration of 372 mg (Equivalent to 200 mg Isavuconazole) via Nasogastric (NG) Tube in Healthy Adult Subjects Under Fasted Conditions
	CRESEMBA IV Solution via NG Tube		CRESEMBA Oral Capsules		NG Tube/Oral Capsule
Pharmacokinetic Parameter	N	Mean (%CV)	N	Mean (%CV)	GMR (90% CI)
C_max(mg/L)	13	2.3 (23.6)	13	2.2 (26.7)	105.34 (89-124)
AUC_0-72hr (mg·hr/L)	13	34.9 (22.1)	13	35.8 (24.6)	97.81 (93-103)
AUC_0-∞ (mg·hr/L)	12	98.1 (44.5)	12	100.1 (46.8)	99.27 (93-106)
GMR = Geometric least-squares mean ratio; CI = confidence interval

Effect of Food

Coadministration of CRESEMBA equivalent to isavuconazole 400 mg oral dose with a high-fat meal reduced isavuconazole C_maxby 9% and increased AUC by 9%. CRESEMBA can be taken with or without food.

Distribution

Elimination

Metabolism

in vitro

In vivo

studies indicate that CYP3A4, CYP3A5 and subsequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole.

Excretion

Renal excretion of isavuconazole itself was less than 1% of the dose administered.

Special populations

Geriatric Patients

Pediatric Patients

Table 8. Derived Steady State Isavuconazole AUC (mg•hr/L) values in Pediatric Patients, by Age Group
Dosage	15 mg/kg Estimated AUCss values of 15 mg/kg that were derived from existing values of pediatric patients that received 10 mg/kg of CRESEMBA for injection administered intravenously.	10 mg/kg CRESEMBA for injection administered intravenously.	10 mg/kg or Maximum Dose of 372 mg CRESEMBA for injection administered intravenously or CRESEMBA capsules administered orally.
Age Group	1 to < 3 years (n=5)	3 to < 6 years (n=10)	6 to < 12 years (n=29)	12 to < 18 years (n=29)
Mean	80.2	103.3	97.3	104.2
Median	64.3	110.3	87.7	97.7
Minimum - Maximum	53.7 - 155	51.5 – 159.1	37.8– 153.8	35.5 – 215.6

Race

Gender

AUC estimates were similar between young female and male subjects (18 years to 45 years). There was a difference in AUC for elderly females

(see

Geriatric

section above)

. No dose adjustment is required based on gender.

Patients with Renal Impairment

Isavuconazole is not readily dialyzable. A dose adjustment is not warranted in patients with ESRD.

Patients with Hepatic Impairment

Drug Interaction Studies

In Vitro Studies

CYP450 Enzymes:

Isavuconazole is a substrate of CYP3A4 and CYP3A5. Isavuconazole is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Isavuconazole is an inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9.

Transporter Systems:

Isavuconazole is an inhibitor of P-gp-, BCRP- and OCT2.

Clinical Studies and Model-Informed Approaches

The effects of ketoconazole, rifampin, lopinavir/ritonavir, and esomeprazole on isavuconazole are shown inFigure 1.

Ketoconazole:

Lopinavir/Ritonavir:

Rifampin:

Figure 1. The Effect of Coadministered Drugs on Isavuconazole Exposure

CYP3A4 Substrates:

CRESEMBA increased the systemic exposure of sensitive CYP3A4 substrates midazolam, sirolimus and tacrolimus approximately 2-fold, and therefore CRESEMBA is a moderate inhibitor of CYP3A4.

Figure 2. The Effect of Isavuconazole on Coadministered CYP3A4 Substrate Medications

The effects of isavuconazole on other CYP substrates: caffeine, bupropion, methadone, repaglinide, warfarin, omeprazole, and dextromethorphan, are shown inFigure 3.

Figure 3. The Effect of Isavuconazole on Exposure of Coadministered CYP Substrate Medications

The effects of isavuconazole on the substrates of UGT and transporters: mycophenolate mofetil (MMF), methotrexate, metformin, and digoxin are shown inFigure 4.

Figure 4. The Effect of Isavuconazole on Exposure on the Substrates of UGT and Transporters

Vincristine:

Vincristine (P-gp substrate) exposure is predicted to increase by less than 2-fold in pediatric and adult patients following concomitant administration with CRESEMBA.

(

12.3 Pharmacokinetics

General Pharmacokinetics

Table 6. Steady State Pharmacokinetic Parameters of Isavuconazole Following Administration of 186 mg CRESEMBA Capsules
Parameter	CRESEMBA 186 mg 2 Capsules Each capsule contains the equivalent of 100 mg of isavuconazole. (n = 37)	CRESEMBA 186 mg 6 Capsules (n = 32)
C_max(mg/L)
Mean SD CV %	7.5 1.9 25.2	20.0 3.6 17.9
t_max(hr)
Median Range	3.0 2.0 – 4.0	4.0 2.0 – 4.0
AUC (mg•hr/L)
Mean SD CV %	121.4 35.8 29.5	352.8 72.0 20.4

Absorption

CRESEMBA given orally as an intravenous solution administered via nasogastric (NG) tube provides systemic isavuconazole exposure that is similar to the oral capsule (Table 7).

Table 7. Statistical Comparison of Plasma Pharmacokinetics of Isavuconazole Following Single Oral Dose Administration of 2 Capsules of 186 mg (Equivalent to 200 mg Isavuconazole) and Single Intravenous Solution Dose Administration of 372 mg (Equivalent to 200 mg Isavuconazole) via Nasogastric (NG) Tube in Healthy Adult Subjects Under Fasted Conditions
	CRESEMBA IV Solution via NG Tube		CRESEMBA Oral Capsules		NG Tube/Oral Capsule
Pharmacokinetic Parameter	N	Mean (%CV)	N	Mean (%CV)	GMR (90% CI)
C_max(mg/L)	13	2.3 (23.6)	13	2.2 (26.7)	105.34 (89-124)
AUC_0-72hr (mg·hr/L)	13	34.9 (22.1)	13	35.8 (24.6)	97.81 (93-103)
AUC_0-∞ (mg·hr/L)	12	98.1 (44.5)	12	100.1 (46.8)	99.27 (93-106)
GMR = Geometric least-squares mean ratio; CI = confidence interval

Effect of Food

Coadministration of CRESEMBA equivalent to isavuconazole 400 mg oral dose with a high-fat meal reduced isavuconazole C_maxby 9% and increased AUC by 9%. CRESEMBA can be taken with or without food.

Distribution

Elimination

Metabolism

in vitro

In vivo

studies indicate that CYP3A4, CYP3A5 and subsequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole.

Excretion

Renal excretion of isavuconazole itself was less than 1% of the dose administered.

Special populations

Geriatric Patients

Pediatric Patients

Table 8. Derived Steady State Isavuconazole AUC (mg•hr/L) values in Pediatric Patients, by Age Group
Dosage	15 mg/kg Estimated AUCss values of 15 mg/kg that were derived from existing values of pediatric patients that received 10 mg/kg of CRESEMBA for injection administered intravenously.	10 mg/kg CRESEMBA for injection administered intravenously.	10 mg/kg or Maximum Dose of 372 mg CRESEMBA for injection administered intravenously or CRESEMBA capsules administered orally.
Age Group	1 to < 3 years (n=5)	3 to < 6 years (n=10)	6 to < 12 years (n=29)	12 to < 18 years (n=29)
Mean	80.2	103.3	97.3	104.2
Median	64.3	110.3	87.7	97.7
Minimum - Maximum	53.7 - 155	51.5 – 159.1	37.8– 153.8	35.5 – 215.6

Race

Gender

AUC estimates were similar between young female and male subjects (18 years to 45 years). There was a difference in AUC for elderly females

(see

Geriatric

section above)

. No dose adjustment is required based on gender.

Patients with Renal Impairment

Isavuconazole is not readily dialyzable. A dose adjustment is not warranted in patients with ESRD.

Patients with Hepatic Impairment

Drug Interaction Studies

In Vitro Studies

CYP450 Enzymes:

Isavuconazole is a substrate of CYP3A4 and CYP3A5. Isavuconazole is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Isavuconazole is an inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9.

Transporter Systems:

Isavuconazole is an inhibitor of P-gp-, BCRP- and OCT2.

Clinical Studies and Model-Informed Approaches

The effects of ketoconazole, rifampin, lopinavir/ritonavir, and esomeprazole on isavuconazole are shown inFigure 1.

Ketoconazole:

Lopinavir/Ritonavir:

Rifampin:

Figure 1. The Effect of Coadministered Drugs on Isavuconazole Exposure

CYP3A4 Substrates:

CRESEMBA increased the systemic exposure of sensitive CYP3A4 substrates midazolam, sirolimus and tacrolimus approximately 2-fold, and therefore CRESEMBA is a moderate inhibitor of CYP3A4.

Figure 2. The Effect of Isavuconazole on Coadministered CYP3A4 Substrate Medications

The effects of isavuconazole on other CYP substrates: caffeine, bupropion, methadone, repaglinide, warfarin, omeprazole, and dextromethorphan, are shown inFigure 3.

Figure 3. The Effect of Isavuconazole on Exposure of Coadministered CYP Substrate Medications

The effects of isavuconazole on the substrates of UGT and transporters: mycophenolate mofetil (MMF), methotrexate, metformin, and digoxin are shown inFigure 4.

Figure 4. The Effect of Isavuconazole on Exposure on the Substrates of UGT and Transporters

Vincristine:

Vincristine (P-gp substrate) exposure is predicted to increase by less than 2-fold in pediatric and adult patients following concomitant administration with CRESEMBA.

)]

Rifampin

Contraindicate coadministration of all potent CYP3A4 inducers

There is a 97% decrease in exposure of isavuconazole upon coadministration with rifampin

[see

12.3 Pharmacokinetics

General Pharmacokinetics

Table 6. Steady State Pharmacokinetic Parameters of Isavuconazole Following Administration of 186 mg CRESEMBA Capsules
Parameter	CRESEMBA 186 mg 2 Capsules Each capsule contains the equivalent of 100 mg of isavuconazole. (n = 37)	CRESEMBA 186 mg 6 Capsules (n = 32)
C_max(mg/L)
Mean SD CV %	7.5 1.9 25.2	20.0 3.6 17.9
t_max(hr)
Median Range	3.0 2.0 – 4.0	4.0 2.0 – 4.0
AUC (mg•hr/L)
Mean SD CV %	121.4 35.8 29.5	352.8 72.0 20.4

Absorption

CRESEMBA given orally as an intravenous solution administered via nasogastric (NG) tube provides systemic isavuconazole exposure that is similar to the oral capsule (Table 7).

Table 7. Statistical Comparison of Plasma Pharmacokinetics of Isavuconazole Following Single Oral Dose Administration of 2 Capsules of 186 mg (Equivalent to 200 mg Isavuconazole) and Single Intravenous Solution Dose Administration of 372 mg (Equivalent to 200 mg Isavuconazole) via Nasogastric (NG) Tube in Healthy Adult Subjects Under Fasted Conditions
	CRESEMBA IV Solution via NG Tube		CRESEMBA Oral Capsules		NG Tube/Oral Capsule
Pharmacokinetic Parameter	N	Mean (%CV)	N	Mean (%CV)	GMR (90% CI)
C_max(mg/L)	13	2.3 (23.6)	13	2.2 (26.7)	105.34 (89-124)
AUC_0-72hr (mg·hr/L)	13	34.9 (22.1)	13	35.8 (24.6)	97.81 (93-103)
AUC_0-∞ (mg·hr/L)	12	98.1 (44.5)	12	100.1 (46.8)	99.27 (93-106)
GMR = Geometric least-squares mean ratio; CI = confidence interval

Effect of Food

Coadministration of CRESEMBA equivalent to isavuconazole 400 mg oral dose with a high-fat meal reduced isavuconazole C_maxby 9% and increased AUC by 9%. CRESEMBA can be taken with or without food.

Distribution

Elimination

Metabolism

in vitro

In vivo

studies indicate that CYP3A4, CYP3A5 and subsequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole.

Excretion

Renal excretion of isavuconazole itself was less than 1% of the dose administered.

Special populations

Geriatric Patients

Pediatric Patients

Table 8. Derived Steady State Isavuconazole AUC (mg•hr/L) values in Pediatric Patients, by Age Group
Dosage	15 mg/kg Estimated AUCss values of 15 mg/kg that were derived from existing values of pediatric patients that received 10 mg/kg of CRESEMBA for injection administered intravenously.	10 mg/kg CRESEMBA for injection administered intravenously.	10 mg/kg or Maximum Dose of 372 mg CRESEMBA for injection administered intravenously or CRESEMBA capsules administered orally.
Age Group	1 to < 3 years (n=5)	3 to < 6 years (n=10)	6 to < 12 years (n=29)	12 to < 18 years (n=29)
Mean	80.2	103.3	97.3	104.2
Median	64.3	110.3	87.7	97.7
Minimum - Maximum	53.7 - 155	51.5 – 159.1	37.8– 153.8	35.5 – 215.6

Race

Gender

AUC estimates were similar between young female and male subjects (18 years to 45 years). There was a difference in AUC for elderly females

(see

Geriatric

section above)

. No dose adjustment is required based on gender.

Patients with Renal Impairment

Isavuconazole is not readily dialyzable. A dose adjustment is not warranted in patients with ESRD.

Patients with Hepatic Impairment

Drug Interaction Studies

In Vitro Studies

CYP450 Enzymes:

Isavuconazole is a substrate of CYP3A4 and CYP3A5. Isavuconazole is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Isavuconazole is an inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9.

Transporter Systems:

Isavuconazole is an inhibitor of P-gp-, BCRP- and OCT2.

Clinical Studies and Model-Informed Approaches

The effects of ketoconazole, rifampin, lopinavir/ritonavir, and esomeprazole on isavuconazole are shown inFigure 1.

Ketoconazole:

Lopinavir/Ritonavir:

Rifampin:

Figure 1. The Effect of Coadministered Drugs on Isavuconazole Exposure

CYP3A4 Substrates:

CRESEMBA increased the systemic exposure of sensitive CYP3A4 substrates midazolam, sirolimus and tacrolimus approximately 2-fold, and therefore CRESEMBA is a moderate inhibitor of CYP3A4.

Figure 2. The Effect of Isavuconazole on Coadministered CYP3A4 Substrate Medications

The effects of isavuconazole on other CYP substrates: caffeine, bupropion, methadone, repaglinide, warfarin, omeprazole, and dextromethorphan, are shown inFigure 3.

Figure 3. The Effect of Isavuconazole on Exposure of Coadministered CYP Substrate Medications

The effects of isavuconazole on the substrates of UGT and transporters: mycophenolate mofetil (MMF), methotrexate, metformin, and digoxin are shown inFigure 4.

Figure 4. The Effect of Isavuconazole on Exposure on the Substrates of UGT and Transporters

Vincristine:

Vincristine (P-gp substrate) exposure is predicted to increase by less than 2-fold in pediatric and adult patients following concomitant administration with CRESEMBA.

(

12.3 Pharmacokinetics

General Pharmacokinetics

Table 6. Steady State Pharmacokinetic Parameters of Isavuconazole Following Administration of 186 mg CRESEMBA Capsules
Parameter	CRESEMBA 186 mg 2 Capsules Each capsule contains the equivalent of 100 mg of isavuconazole. (n = 37)	CRESEMBA 186 mg 6 Capsules (n = 32)
C_max(mg/L)
Mean SD CV %	7.5 1.9 25.2	20.0 3.6 17.9
t_max(hr)
Median Range	3.0 2.0 – 4.0	4.0 2.0 – 4.0
AUC (mg•hr/L)
Mean SD CV %	121.4 35.8 29.5	352.8 72.0 20.4

Absorption

CRESEMBA given orally as an intravenous solution administered via nasogastric (NG) tube provides systemic isavuconazole exposure that is similar to the oral capsule (Table 7).

Table 7. Statistical Comparison of Plasma Pharmacokinetics of Isavuconazole Following Single Oral Dose Administration of 2 Capsules of 186 mg (Equivalent to 200 mg Isavuconazole) and Single Intravenous Solution Dose Administration of 372 mg (Equivalent to 200 mg Isavuconazole) via Nasogastric (NG) Tube in Healthy Adult Subjects Under Fasted Conditions
	CRESEMBA IV Solution via NG Tube		CRESEMBA Oral Capsules		NG Tube/Oral Capsule
Pharmacokinetic Parameter	N	Mean (%CV)	N	Mean (%CV)	GMR (90% CI)
C_max(mg/L)	13	2.3 (23.6)	13	2.2 (26.7)	105.34 (89-124)
AUC_0-72hr (mg·hr/L)	13	34.9 (22.1)	13	35.8 (24.6)	97.81 (93-103)
AUC_0-∞ (mg·hr/L)	12	98.1 (44.5)	12	100.1 (46.8)	99.27 (93-106)
GMR = Geometric least-squares mean ratio; CI = confidence interval

Effect of Food

Coadministration of CRESEMBA equivalent to isavuconazole 400 mg oral dose with a high-fat meal reduced isavuconazole C_maxby 9% and increased AUC by 9%. CRESEMBA can be taken with or without food.

Distribution

Elimination

Metabolism

in vitro

In vivo

studies indicate that CYP3A4, CYP3A5 and subsequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole.

Excretion

Renal excretion of isavuconazole itself was less than 1% of the dose administered.

Special populations

Geriatric Patients

Pediatric Patients

Table 8. Derived Steady State Isavuconazole AUC (mg•hr/L) values in Pediatric Patients, by Age Group
Dosage	15 mg/kg Estimated AUCss values of 15 mg/kg that were derived from existing values of pediatric patients that received 10 mg/kg of CRESEMBA for injection administered intravenously.	10 mg/kg CRESEMBA for injection administered intravenously.	10 mg/kg or Maximum Dose of 372 mg CRESEMBA for injection administered intravenously or CRESEMBA capsules administered orally.
Age Group	1 to < 3 years (n=5)	3 to < 6 years (n=10)	6 to < 12 years (n=29)	12 to < 18 years (n=29)
Mean	80.2	103.3	97.3	104.2
Median	64.3	110.3	87.7	97.7
Minimum - Maximum	53.7 - 155	51.5 – 159.1	37.8– 153.8	35.5 – 215.6

Race

Gender

AUC estimates were similar between young female and male subjects (18 years to 45 years). There was a difference in AUC for elderly females

(see

Geriatric

section above)

. No dose adjustment is required based on gender.

Patients with Renal Impairment

Isavuconazole is not readily dialyzable. A dose adjustment is not warranted in patients with ESRD.

Patients with Hepatic Impairment

Drug Interaction Studies

In Vitro Studies

CYP450 Enzymes:

Isavuconazole is a substrate of CYP3A4 and CYP3A5. Isavuconazole is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Isavuconazole is an inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9.

Transporter Systems:

Isavuconazole is an inhibitor of P-gp-, BCRP- and OCT2.

Clinical Studies and Model-Informed Approaches

The effects of ketoconazole, rifampin, lopinavir/ritonavir, and esomeprazole on isavuconazole are shown inFigure 1.

Ketoconazole:

Lopinavir/Ritonavir:

Rifampin:

Figure 1. The Effect of Coadministered Drugs on Isavuconazole Exposure

CYP3A4 Substrates:

CRESEMBA increased the systemic exposure of sensitive CYP3A4 substrates midazolam, sirolimus and tacrolimus approximately 2-fold, and therefore CRESEMBA is a moderate inhibitor of CYP3A4.

Figure 2. The Effect of Isavuconazole on Coadministered CYP3A4 Substrate Medications

The effects of isavuconazole on other CYP substrates: caffeine, bupropion, methadone, repaglinide, warfarin, omeprazole, and dextromethorphan, are shown inFigure 3.

Figure 3. The Effect of Isavuconazole on Exposure of Coadministered CYP Substrate Medications

The effects of isavuconazole on the substrates of UGT and transporters: mycophenolate mofetil (MMF), methotrexate, metformin, and digoxin are shown inFigure 4.

Figure 4. The Effect of Isavuconazole on Exposure on the Substrates of UGT and Transporters

Vincristine:

Vincristine (P-gp substrate) exposure is predicted to increase by less than 2-fold in pediatric and adult patients following concomitant administration with CRESEMBA.

)]

CYP3A4 Substrates:

CRESEMBA increased the systemic exposure of sensitive CYP3A4 substrates midazolam, sirolimus and tacrolimus approximately 2-fold, and therefore CRESEMBA is a moderate inhibitor of CYP3A4.

The effects of isavuconazole on other CYP substrates: caffeine, bupropion, methadone, repaglinide, warfarin, omeprazole, and dextromethorphan, are shown inFigure 3.

The effects of isavuconazole on the substrates of UGT and transporters: mycophenolate mofetil (MMF), methotrexate, metformin, and digoxin are shown inFigure 4.

Vincristine:

Vincristine (P-gp substrate) exposure is predicted to increase by less than 2-fold in pediatric and adult patients following concomitant administration with CRESEMBA.

(

12.3 Pharmacokinetics

General Pharmacokinetics

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

12.3 Pharmacokinetics

General Pharmacokinetics

Table 6. Steady State Pharmacokinetic Parameters of Isavuconazole Following Administration of 186 mg CRESEMBA Capsules
Parameter	CRESEMBA 186 mg 2 Capsules Each capsule contains the equivalent of 100 mg of isavuconazole. (n = 37)	CRESEMBA 186 mg 6 Capsules (n = 32)
C_max(mg/L)
Mean SD CV %	7.5 1.9 25.2	20.0 3.6 17.9
t_max(hr)
Median Range	3.0 2.0 – 4.0	4.0 2.0 – 4.0
AUC (mg•hr/L)
Mean SD CV %	121.4 35.8 29.5	352.8 72.0 20.4

Absorption

CRESEMBA given orally as an intravenous solution administered via nasogastric (NG) tube provides systemic isavuconazole exposure that is similar to the oral capsule (Table 7).

Table 7. Statistical Comparison of Plasma Pharmacokinetics of Isavuconazole Following Single Oral Dose Administration of 2 Capsules of 186 mg (Equivalent to 200 mg Isavuconazole) and Single Intravenous Solution Dose Administration of 372 mg (Equivalent to 200 mg Isavuconazole) via Nasogastric (NG) Tube in Healthy Adult Subjects Under Fasted Conditions
	CRESEMBA IV Solution via NG Tube		CRESEMBA Oral Capsules		NG Tube/Oral Capsule
Pharmacokinetic Parameter	N	Mean (%CV)	N	Mean (%CV)	GMR (90% CI)
C_max(mg/L)	13	2.3 (23.6)	13	2.2 (26.7)	105.34 (89-124)
AUC_0-72hr (mg·hr/L)	13	34.9 (22.1)	13	35.8 (24.6)	97.81 (93-103)
AUC_0-∞ (mg·hr/L)	12	98.1 (44.5)	12	100.1 (46.8)	99.27 (93-106)
GMR = Geometric least-squares mean ratio; CI = confidence interval

Effect of Food

Coadministration of CRESEMBA equivalent to isavuconazole 400 mg oral dose with a high-fat meal reduced isavuconazole C_maxby 9% and increased AUC by 9%. CRESEMBA can be taken with or without food.

Distribution

Elimination

Metabolism

in vitro

In vivo

studies indicate that CYP3A4, CYP3A5 and subsequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole.

Excretion

Renal excretion of isavuconazole itself was less than 1% of the dose administered.

Special populations

Geriatric Patients

Pediatric Patients

Table 8. Derived Steady State Isavuconazole AUC (mg•hr/L) values in Pediatric Patients, by Age Group
Dosage	15 mg/kg Estimated AUCss values of 15 mg/kg that were derived from existing values of pediatric patients that received 10 mg/kg of CRESEMBA for injection administered intravenously.	10 mg/kg CRESEMBA for injection administered intravenously.	10 mg/kg or Maximum Dose of 372 mg CRESEMBA for injection administered intravenously or CRESEMBA capsules administered orally.
Age Group	1 to < 3 years (n=5)	3 to < 6 years (n=10)	6 to < 12 years (n=29)	12 to < 18 years (n=29)
Mean	80.2	103.3	97.3	104.2
Median	64.3	110.3	87.7	97.7
Minimum - Maximum	53.7 - 155	51.5 – 159.1	37.8– 153.8	35.5 – 215.6

Race

Gender

AUC estimates were similar between young female and male subjects (18 years to 45 years). There was a difference in AUC for elderly females

(see

Geriatric

section above)

. No dose adjustment is required based on gender.

Patients with Renal Impairment

Isavuconazole is not readily dialyzable. A dose adjustment is not warranted in patients with ESRD.

Patients with Hepatic Impairment

Drug Interaction Studies

In Vitro Studies

CYP450 Enzymes:

Isavuconazole is a substrate of CYP3A4 and CYP3A5. Isavuconazole is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Isavuconazole is an inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9.

Transporter Systems:

Isavuconazole is an inhibitor of P-gp-, BCRP- and OCT2.

Clinical Studies and Model-Informed Approaches

The effects of ketoconazole, rifampin, lopinavir/ritonavir, and esomeprazole on isavuconazole are shown inFigure 1.

Ketoconazole:

Lopinavir/Ritonavir:

Rifampin:

Table 6. Steady State Pharmacokinetic Parameters of Isavuconazole Following Administration of 186 mg CRESEMBA Capsules
Parameter	CRESEMBA 186 mg 2 Capsules Each capsule contains the equivalent of 100 mg of isavuconazole. (n = 37)	CRESEMBA 186 mg 6 Capsules (n = 32)
C_max(mg/L)
Mean SD CV %	7.5 1.9 25.2	20.0 3.6 17.9
t_max(hr)
Median Range	3.0 2.0 – 4.0	4.0 2.0 – 4.0
AUC (mg•hr/L)
Mean SD CV %	121.4 35.8 29.5	352.8 72.0 20.4

Absorption

CRESEMBA given orally as an intravenous solution administered via nasogastric (NG) tube provides systemic isavuconazole exposure that is similar to the oral capsule (Table 7).

Table 7. Statistical Comparison of Plasma Pharmacokinetics of Isavuconazole Following Single Oral Dose Administration of 2 Capsules of 186 mg (Equivalent to 200 mg Isavuconazole) and Single Intravenous Solution Dose Administration of 372 mg (Equivalent to 200 mg Isavuconazole) via Nasogastric (NG) Tube in Healthy Adult Subjects Under Fasted Conditions
	CRESEMBA IV Solution via NG Tube		CRESEMBA Oral Capsules		NG Tube/Oral Capsule
Pharmacokinetic Parameter	N	Mean (%CV)	N	Mean (%CV)	GMR (90% CI)
C_max(mg/L)	13	2.3 (23.6)	13	2.2 (26.7)	105.34 (89-124)
AUC_0-72hr (mg·hr/L)	13	34.9 (22.1)	13	35.8 (24.6)	97.81 (93-103)
AUC_0-∞ (mg·hr/L)	12	98.1 (44.5)	12	100.1 (46.8)	99.27 (93-106)
GMR = Geometric least-squares mean ratio; CI = confidence interval

Effect of Food

Coadministration of CRESEMBA equivalent to isavuconazole 400 mg oral dose with a high-fat meal reduced isavuconazole C_maxby 9% and increased AUC by 9%. CRESEMBA can be taken with or without food.

Distribution

Elimination

Metabolism

in vitro

In vivo

studies indicate that CYP3A4, CYP3A5 and subsequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole.

Excretion

Renal excretion of isavuconazole itself was less than 1% of the dose administered.

Special populations

Geriatric Patients

Pediatric Patients

Table 8. Derived Steady State Isavuconazole AUC (mg•hr/L) values in Pediatric Patients, by Age Group
Dosage	15 mg/kg Estimated AUCss values of 15 mg/kg that were derived from existing values of pediatric patients that received 10 mg/kg of CRESEMBA for injection administered intravenously.	10 mg/kg CRESEMBA for injection administered intravenously.	10 mg/kg or Maximum Dose of 372 mg CRESEMBA for injection administered intravenously or CRESEMBA capsules administered orally.
Age Group	1 to < 3 years (n=5)	3 to < 6 years (n=10)	6 to < 12 years (n=29)	12 to < 18 years (n=29)
Mean	80.2	103.3	97.3	104.2
Median	64.3	110.3	87.7	97.7
Minimum - Maximum	53.7 - 155	51.5 – 159.1	37.8– 153.8	35.5 – 215.6

Race

Gender

AUC estimates were similar between young female and male subjects (18 years to 45 years). There was a difference in AUC for elderly females

(see

Geriatric

section above)

. No dose adjustment is required based on gender.

Patients with Renal Impairment

Isavuconazole is not readily dialyzable. A dose adjustment is not warranted in patients with ESRD.

Patients with Hepatic Impairment

Drug Interaction Studies

In Vitro Studies

CYP450 Enzymes:

Isavuconazole is a substrate of CYP3A4 and CYP3A5. Isavuconazole is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Isavuconazole is an inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9.

Transporter Systems:

Isavuconazole is an inhibitor of P-gp-, BCRP- and OCT2.

Clinical Studies and Model-Informed Approaches

The effects of ketoconazole, rifampin, lopinavir/ritonavir, and esomeprazole on isavuconazole are shown inFigure 1.

Ketoconazole:

Lopinavir/Ritonavir:

Rifampin:

Figure 1. The Effect of Coadministered Drugs on Isavuconazole Exposure

CYP3A4 Substrates:

CRESEMBA increased the systemic exposure of sensitive CYP3A4 substrates midazolam, sirolimus and tacrolimus approximately 2-fold, and therefore CRESEMBA is a moderate inhibitor of CYP3A4.

Figure 2. The Effect of Isavuconazole on Coadministered CYP3A4 Substrate Medications

The effects of isavuconazole on other CYP substrates: caffeine, bupropion, methadone, repaglinide, warfarin, omeprazole, and dextromethorphan, are shown inFigure 3.

Figure 3. The Effect of Isavuconazole on Exposure of Coadministered CYP Substrate Medications

The effects of isavuconazole on the substrates of UGT and transporters: mycophenolate mofetil (MMF), methotrexate, metformin, and digoxin are shown inFigure 4.

Figure 4. The Effect of Isavuconazole on Exposure on the Substrates of UGT and Transporters

Vincristine:

Vincristine (P-gp substrate) exposure is predicted to increase by less than 2-fold in pediatric and adult patients following concomitant administration with CRESEMBA.

)].

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

12.3 Pharmacokinetics

General Pharmacokinetics

Table 6. Steady State Pharmacokinetic Parameters of Isavuconazole Following Administration of 186 mg CRESEMBA Capsules
Parameter	CRESEMBA 186 mg 2 Capsules Each capsule contains the equivalent of 100 mg of isavuconazole. (n = 37)	CRESEMBA 186 mg 6 Capsules (n = 32)
C_max(mg/L)
Mean SD CV %	7.5 1.9 25.2	20.0 3.6 17.9
t_max(hr)
Median Range	3.0 2.0 – 4.0	4.0 2.0 – 4.0
AUC (mg•hr/L)
Mean SD CV %	121.4 35.8 29.5	352.8 72.0 20.4

Absorption

CRESEMBA given orally as an intravenous solution administered via nasogastric (NG) tube provides systemic isavuconazole exposure that is similar to the oral capsule (Table 7).

Table 7. Statistical Comparison of Plasma Pharmacokinetics of Isavuconazole Following Single Oral Dose Administration of 2 Capsules of 186 mg (Equivalent to 200 mg Isavuconazole) and Single Intravenous Solution Dose Administration of 372 mg (Equivalent to 200 mg Isavuconazole) via Nasogastric (NG) Tube in Healthy Adult Subjects Under Fasted Conditions
	CRESEMBA IV Solution via NG Tube		CRESEMBA Oral Capsules		NG Tube/Oral Capsule
Pharmacokinetic Parameter	N	Mean (%CV)	N	Mean (%CV)	GMR (90% CI)
C_max(mg/L)	13	2.3 (23.6)	13	2.2 (26.7)	105.34 (89-124)
AUC_0-72hr (mg·hr/L)	13	34.9 (22.1)	13	35.8 (24.6)	97.81 (93-103)
AUC_0-∞ (mg·hr/L)	12	98.1 (44.5)	12	100.1 (46.8)	99.27 (93-106)
GMR = Geometric least-squares mean ratio; CI = confidence interval

Effect of Food

Coadministration of CRESEMBA equivalent to isavuconazole 400 mg oral dose with a high-fat meal reduced isavuconazole C_maxby 9% and increased AUC by 9%. CRESEMBA can be taken with or without food.

Distribution

Elimination

Metabolism

in vitro

In vivo

studies indicate that CYP3A4, CYP3A5 and subsequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole.

Excretion

Renal excretion of isavuconazole itself was less than 1% of the dose administered.

Special populations

Geriatric Patients

Pediatric Patients

Table 8. Derived Steady State Isavuconazole AUC (mg•hr/L) values in Pediatric Patients, by Age Group
Dosage	15 mg/kg Estimated AUCss values of 15 mg/kg that were derived from existing values of pediatric patients that received 10 mg/kg of CRESEMBA for injection administered intravenously.	10 mg/kg CRESEMBA for injection administered intravenously.	10 mg/kg or Maximum Dose of 372 mg CRESEMBA for injection administered intravenously or CRESEMBA capsules administered orally.
Age Group	1 to < 3 years (n=5)	3 to < 6 years (n=10)	6 to < 12 years (n=29)	12 to < 18 years (n=29)
Mean	80.2	103.3	97.3	104.2
Median	64.3	110.3	87.7	97.7
Minimum - Maximum	53.7 - 155	51.5 – 159.1	37.8– 153.8	35.5 – 215.6

Race

Gender

AUC estimates were similar between young female and male subjects (18 years to 45 years). There was a difference in AUC for elderly females

(see

Geriatric

section above)

. No dose adjustment is required based on gender.

Patients with Renal Impairment

Isavuconazole is not readily dialyzable. A dose adjustment is not warranted in patients with ESRD.

Patients with Hepatic Impairment

Drug Interaction Studies

In Vitro Studies

CYP450 Enzymes:

Isavuconazole is a substrate of CYP3A4 and CYP3A5. Isavuconazole is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Isavuconazole is an inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9.

Transporter Systems:

Isavuconazole is an inhibitor of P-gp-, BCRP- and OCT2.

Clinical Studies and Model-Informed Approaches

The effects of ketoconazole, rifampin, lopinavir/ritonavir, and esomeprazole on isavuconazole are shown inFigure 1.

Ketoconazole:

Lopinavir/Ritonavir:

Rifampin:

Figure 1. The Effect of Coadministered Drugs on Isavuconazole Exposure

CYP3A4 Substrates:

CRESEMBA increased the systemic exposure of sensitive CYP3A4 substrates midazolam, sirolimus and tacrolimus approximately 2-fold, and therefore CRESEMBA is a moderate inhibitor of CYP3A4.

Figure 2. The Effect of Isavuconazole on Coadministered CYP3A4 Substrate Medications

The effects of isavuconazole on other CYP substrates: caffeine, bupropion, methadone, repaglinide, warfarin, omeprazole, and dextromethorphan, are shown inFigure 3.

Figure 3. The Effect of Isavuconazole on Exposure of Coadministered CYP Substrate Medications

The effects of isavuconazole on the substrates of UGT and transporters: mycophenolate mofetil (MMF), methotrexate, metformin, and digoxin are shown inFigure 4.

Figure 4. The Effect of Isavuconazole on Exposure on the Substrates of UGT and Transporters

Vincristine:

Vincristine (P-gp substrate) exposure is predicted to increase by less than 2-fold in pediatric and adult patients following concomitant administration with CRESEMBA.

(

12.3 Pharmacokinetics

General Pharmacokinetics

Table 6. Steady State Pharmacokinetic Parameters of Isavuconazole Following Administration of 186 mg CRESEMBA Capsules
Parameter	CRESEMBA 186 mg 2 Capsules Each capsule contains the equivalent of 100 mg of isavuconazole. (n = 37)	CRESEMBA 186 mg 6 Capsules (n = 32)
C_max(mg/L)
Mean SD CV %	7.5 1.9 25.2	20.0 3.6 17.9
t_max(hr)
Median Range	3.0 2.0 – 4.0	4.0 2.0 – 4.0
AUC (mg•hr/L)
Mean SD CV %	121.4 35.8 29.5	352.8 72.0 20.4

Absorption

CRESEMBA given orally as an intravenous solution administered via nasogastric (NG) tube provides systemic isavuconazole exposure that is similar to the oral capsule (Table 7).

Table 7. Statistical Comparison of Plasma Pharmacokinetics of Isavuconazole Following Single Oral Dose Administration of 2 Capsules of 186 mg (Equivalent to 200 mg Isavuconazole) and Single Intravenous Solution Dose Administration of 372 mg (Equivalent to 200 mg Isavuconazole) via Nasogastric (NG) Tube in Healthy Adult Subjects Under Fasted Conditions
	CRESEMBA IV Solution via NG Tube		CRESEMBA Oral Capsules		NG Tube/Oral Capsule
Pharmacokinetic Parameter	N	Mean (%CV)	N	Mean (%CV)	GMR (90% CI)
C_max(mg/L)	13	2.3 (23.6)	13	2.2 (26.7)	105.34 (89-124)
AUC_0-72hr (mg·hr/L)	13	34.9 (22.1)	13	35.8 (24.6)	97.81 (93-103)
AUC_0-∞ (mg·hr/L)	12	98.1 (44.5)	12	100.1 (46.8)	99.27 (93-106)
GMR = Geometric least-squares mean ratio; CI = confidence interval

Effect of Food

Coadministration of CRESEMBA equivalent to isavuconazole 400 mg oral dose with a high-fat meal reduced isavuconazole C_maxby 9% and increased AUC by 9%. CRESEMBA can be taken with or without food.

Distribution

Elimination

Metabolism

in vitro

In vivo

studies indicate that CYP3A4, CYP3A5 and subsequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole.

Excretion

Renal excretion of isavuconazole itself was less than 1% of the dose administered.

Special populations

Geriatric Patients

Pediatric Patients

Table 8. Derived Steady State Isavuconazole AUC (mg•hr/L) values in Pediatric Patients, by Age Group
Dosage	15 mg/kg Estimated AUCss values of 15 mg/kg that were derived from existing values of pediatric patients that received 10 mg/kg of CRESEMBA for injection administered intravenously.	10 mg/kg CRESEMBA for injection administered intravenously.	10 mg/kg or Maximum Dose of 372 mg CRESEMBA for injection administered intravenously or CRESEMBA capsules administered orally.
Age Group	1 to < 3 years (n=5)	3 to < 6 years (n=10)	6 to < 12 years (n=29)	12 to < 18 years (n=29)
Mean	80.2	103.3	97.3	104.2
Median	64.3	110.3	87.7	97.7
Minimum - Maximum	53.7 - 155	51.5 – 159.1	37.8– 153.8	35.5 – 215.6

Race

Gender

AUC estimates were similar between young female and male subjects (18 years to 45 years). There was a difference in AUC for elderly females

(see

Geriatric

section above)

. No dose adjustment is required based on gender.

Patients with Renal Impairment

Isavuconazole is not readily dialyzable. A dose adjustment is not warranted in patients with ESRD.

Patients with Hepatic Impairment

Drug Interaction Studies

In Vitro Studies

CYP450 Enzymes:

Isavuconazole is a substrate of CYP3A4 and CYP3A5. Isavuconazole is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Isavuconazole is an inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9.

Transporter Systems:

Isavuconazole is an inhibitor of P-gp-, BCRP- and OCT2.

Clinical Studies and Model-Informed Approaches

The effects of ketoconazole, rifampin, lopinavir/ritonavir, and esomeprazole on isavuconazole are shown inFigure 1.

Ketoconazole:

Lopinavir/Ritonavir:

Rifampin:

Figure 1. The Effect of Coadministered Drugs on Isavuconazole Exposure

CYP3A4 Substrates:

CRESEMBA increased the systemic exposure of sensitive CYP3A4 substrates midazolam, sirolimus and tacrolimus approximately 2-fold, and therefore CRESEMBA is a moderate inhibitor of CYP3A4.

Figure 2. The Effect of Isavuconazole on Coadministered CYP3A4 Substrate Medications

The effects of isavuconazole on other CYP substrates: caffeine, bupropion, methadone, repaglinide, warfarin, omeprazole, and dextromethorphan, are shown inFigure 3.

Figure 3. The Effect of Isavuconazole on Exposure of Coadministered CYP Substrate Medications

The effects of isavuconazole on the substrates of UGT and transporters: mycophenolate mofetil (MMF), methotrexate, metformin, and digoxin are shown inFigure 4.

Figure 4. The Effect of Isavuconazole on Exposure on the Substrates of UGT and Transporters

Vincristine:

Vincristine (P-gp substrate) exposure is predicted to increase by less than 2-fold in pediatric and adult patients following concomitant administration with CRESEMBA.

)]

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

12.3 Pharmacokinetics

General Pharmacokinetics

Table 6. Steady State Pharmacokinetic Parameters of Isavuconazole Following Administration of 186 mg CRESEMBA Capsules
Parameter	CRESEMBA 186 mg 2 Capsules Each capsule contains the equivalent of 100 mg of isavuconazole. (n = 37)	CRESEMBA 186 mg 6 Capsules (n = 32)
C_max(mg/L)
Mean SD CV %	7.5 1.9 25.2	20.0 3.6 17.9
t_max(hr)
Median Range	3.0 2.0 – 4.0	4.0 2.0 – 4.0
AUC (mg•hr/L)
Mean SD CV %	121.4 35.8 29.5	352.8 72.0 20.4

Absorption

CRESEMBA given orally as an intravenous solution administered via nasogastric (NG) tube provides systemic isavuconazole exposure that is similar to the oral capsule (Table 7).

Table 7. Statistical Comparison of Plasma Pharmacokinetics of Isavuconazole Following Single Oral Dose Administration of 2 Capsules of 186 mg (Equivalent to 200 mg Isavuconazole) and Single Intravenous Solution Dose Administration of 372 mg (Equivalent to 200 mg Isavuconazole) via Nasogastric (NG) Tube in Healthy Adult Subjects Under Fasted Conditions
	CRESEMBA IV Solution via NG Tube		CRESEMBA Oral Capsules		NG Tube/Oral Capsule
Pharmacokinetic Parameter	N	Mean (%CV)	N	Mean (%CV)	GMR (90% CI)
C_max(mg/L)	13	2.3 (23.6)	13	2.2 (26.7)	105.34 (89-124)
AUC_0-72hr (mg·hr/L)	13	34.9 (22.1)	13	35.8 (24.6)	97.81 (93-103)
AUC_0-∞ (mg·hr/L)	12	98.1 (44.5)	12	100.1 (46.8)	99.27 (93-106)
GMR = Geometric least-squares mean ratio; CI = confidence interval

Effect of Food

Coadministration of CRESEMBA equivalent to isavuconazole 400 mg oral dose with a high-fat meal reduced isavuconazole C_maxby 9% and increased AUC by 9%. CRESEMBA can be taken with or without food.

Distribution

Elimination

Metabolism

in vitro

In vivo

studies indicate that CYP3A4, CYP3A5 and subsequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole.

Excretion

Renal excretion of isavuconazole itself was less than 1% of the dose administered.

Special populations

Geriatric Patients

Pediatric Patients

Table 8. Derived Steady State Isavuconazole AUC (mg•hr/L) values in Pediatric Patients, by Age Group
Dosage	15 mg/kg Estimated AUCss values of 15 mg/kg that were derived from existing values of pediatric patients that received 10 mg/kg of CRESEMBA for injection administered intravenously.	10 mg/kg CRESEMBA for injection administered intravenously.	10 mg/kg or Maximum Dose of 372 mg CRESEMBA for injection administered intravenously or CRESEMBA capsules administered orally.
Age Group	1 to < 3 years (n=5)	3 to < 6 years (n=10)	6 to < 12 years (n=29)	12 to < 18 years (n=29)
Mean	80.2	103.3	97.3	104.2
Median	64.3	110.3	87.7	97.7
Minimum - Maximum	53.7 - 155	51.5 – 159.1	37.8– 153.8	35.5 – 215.6

Race

Gender

AUC estimates were similar between young female and male subjects (18 years to 45 years). There was a difference in AUC for elderly females

(see

Geriatric

section above)

. No dose adjustment is required based on gender.

Patients with Renal Impairment

Isavuconazole is not readily dialyzable. A dose adjustment is not warranted in patients with ESRD.

Patients with Hepatic Impairment

Drug Interaction Studies

In Vitro Studies

CYP450 Enzymes:

Isavuconazole is a substrate of CYP3A4 and CYP3A5. Isavuconazole is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Isavuconazole is an inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9.

Transporter Systems:

Isavuconazole is an inhibitor of P-gp-, BCRP- and OCT2.

Clinical Studies and Model-Informed Approaches

The effects of ketoconazole, rifampin, lopinavir/ritonavir, and esomeprazole on isavuconazole are shown inFigure 1.

Ketoconazole:

Lopinavir/Ritonavir:

Rifampin:

Figure 1. The Effect of Coadministered Drugs on Isavuconazole Exposure

CYP3A4 Substrates:

CRESEMBA increased the systemic exposure of sensitive CYP3A4 substrates midazolam, sirolimus and tacrolimus approximately 2-fold, and therefore CRESEMBA is a moderate inhibitor of CYP3A4.

Figure 2. The Effect of Isavuconazole on Coadministered CYP3A4 Substrate Medications

The effects of isavuconazole on other CYP substrates: caffeine, bupropion, methadone, repaglinide, warfarin, omeprazole, and dextromethorphan, are shown inFigure 3.

Figure 3. The Effect of Isavuconazole on Exposure of Coadministered CYP Substrate Medications

The effects of isavuconazole on the substrates of UGT and transporters: mycophenolate mofetil (MMF), methotrexate, metformin, and digoxin are shown inFigure 4.

Figure 4. The Effect of Isavuconazole on Exposure on the Substrates of UGT and Transporters

Vincristine:

Vincristine (P-gp substrate) exposure is predicted to increase by less than 2-fold in pediatric and adult patients following concomitant administration with CRESEMBA.

(

12.3 Pharmacokinetics

General Pharmacokinetics

Table 6. Steady State Pharmacokinetic Parameters of Isavuconazole Following Administration of 186 mg CRESEMBA Capsules
Parameter	CRESEMBA 186 mg 2 Capsules Each capsule contains the equivalent of 100 mg of isavuconazole. (n = 37)	CRESEMBA 186 mg 6 Capsules (n = 32)
C_max(mg/L)
Mean SD CV %	7.5 1.9 25.2	20.0 3.6 17.9
t_max(hr)
Median Range	3.0 2.0 – 4.0	4.0 2.0 – 4.0
AUC (mg•hr/L)
Mean SD CV %	121.4 35.8 29.5	352.8 72.0 20.4

Absorption

CRESEMBA given orally as an intravenous solution administered via nasogastric (NG) tube provides systemic isavuconazole exposure that is similar to the oral capsule (Table 7).

Table 7. Statistical Comparison of Plasma Pharmacokinetics of Isavuconazole Following Single Oral Dose Administration of 2 Capsules of 186 mg (Equivalent to 200 mg Isavuconazole) and Single Intravenous Solution Dose Administration of 372 mg (Equivalent to 200 mg Isavuconazole) via Nasogastric (NG) Tube in Healthy Adult Subjects Under Fasted Conditions
	CRESEMBA IV Solution via NG Tube		CRESEMBA Oral Capsules		NG Tube/Oral Capsule
Pharmacokinetic Parameter	N	Mean (%CV)	N	Mean (%CV)	GMR (90% CI)
C_max(mg/L)	13	2.3 (23.6)	13	2.2 (26.7)	105.34 (89-124)
AUC_0-72hr (mg·hr/L)	13	34.9 (22.1)	13	35.8 (24.6)	97.81 (93-103)
AUC_0-∞ (mg·hr/L)	12	98.1 (44.5)	12	100.1 (46.8)	99.27 (93-106)
GMR = Geometric least-squares mean ratio; CI = confidence interval

Effect of Food

Coadministration of CRESEMBA equivalent to isavuconazole 400 mg oral dose with a high-fat meal reduced isavuconazole C_maxby 9% and increased AUC by 9%. CRESEMBA can be taken with or without food.

Distribution

Elimination

Metabolism

in vitro

In vivo

studies indicate that CYP3A4, CYP3A5 and subsequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole.

Excretion

Renal excretion of isavuconazole itself was less than 1% of the dose administered.

Special populations

Geriatric Patients

Pediatric Patients

Table 8. Derived Steady State Isavuconazole AUC (mg•hr/L) values in Pediatric Patients, by Age Group
Dosage	15 mg/kg Estimated AUCss values of 15 mg/kg that were derived from existing values of pediatric patients that received 10 mg/kg of CRESEMBA for injection administered intravenously.	10 mg/kg CRESEMBA for injection administered intravenously.	10 mg/kg or Maximum Dose of 372 mg CRESEMBA for injection administered intravenously or CRESEMBA capsules administered orally.
Age Group	1 to < 3 years (n=5)	3 to < 6 years (n=10)	6 to < 12 years (n=29)	12 to < 18 years (n=29)
Mean	80.2	103.3	97.3	104.2
Median	64.3	110.3	87.7	97.7
Minimum - Maximum	53.7 - 155	51.5 – 159.1	37.8– 153.8	35.5 – 215.6

Race

Gender

AUC estimates were similar between young female and male subjects (18 years to 45 years). There was a difference in AUC for elderly females

(see

Geriatric

section above)

. No dose adjustment is required based on gender.

Patients with Renal Impairment

Isavuconazole is not readily dialyzable. A dose adjustment is not warranted in patients with ESRD.

Patients with Hepatic Impairment

Drug Interaction Studies

In Vitro Studies

CYP450 Enzymes:

Isavuconazole is a substrate of CYP3A4 and CYP3A5. Isavuconazole is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Isavuconazole is an inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9.

Transporter Systems:

Isavuconazole is an inhibitor of P-gp-, BCRP- and OCT2.

Clinical Studies and Model-Informed Approaches

The effects of ketoconazole, rifampin, lopinavir/ritonavir, and esomeprazole on isavuconazole are shown inFigure 1.

Ketoconazole:

Lopinavir/Ritonavir:

Rifampin:

Figure 1. The Effect of Coadministered Drugs on Isavuconazole Exposure

CYP3A4 Substrates:

CRESEMBA increased the systemic exposure of sensitive CYP3A4 substrates midazolam, sirolimus and tacrolimus approximately 2-fold, and therefore CRESEMBA is a moderate inhibitor of CYP3A4.

Figure 2. The Effect of Isavuconazole on Coadministered CYP3A4 Substrate Medications

The effects of isavuconazole on other CYP substrates: caffeine, bupropion, methadone, repaglinide, warfarin, omeprazole, and dextromethorphan, are shown inFigure 3.

Figure 3. The Effect of Isavuconazole on Exposure of Coadministered CYP Substrate Medications

The effects of isavuconazole on the substrates of UGT and transporters: mycophenolate mofetil (MMF), methotrexate, metformin, and digoxin are shown inFigure 4.

Figure 4. The Effect of Isavuconazole on Exposure on the Substrates of UGT and Transporters

Vincristine:

Vincristine (P-gp substrate) exposure is predicted to increase by less than 2-fold in pediatric and adult patients following concomitant administration with CRESEMBA.

)]

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

12.3 Pharmacokinetics

General Pharmacokinetics

Table 6. Steady State Pharmacokinetic Parameters of Isavuconazole Following Administration of 186 mg CRESEMBA Capsules
Parameter	CRESEMBA 186 mg 2 Capsules Each capsule contains the equivalent of 100 mg of isavuconazole. (n = 37)	CRESEMBA 186 mg 6 Capsules (n = 32)
C_max(mg/L)
Mean SD CV %	7.5 1.9 25.2	20.0 3.6 17.9
t_max(hr)
Median Range	3.0 2.0 – 4.0	4.0 2.0 – 4.0
AUC (mg•hr/L)
Mean SD CV %	121.4 35.8 29.5	352.8 72.0 20.4

Absorption

CRESEMBA given orally as an intravenous solution administered via nasogastric (NG) tube provides systemic isavuconazole exposure that is similar to the oral capsule (Table 7).

Table 7. Statistical Comparison of Plasma Pharmacokinetics of Isavuconazole Following Single Oral Dose Administration of 2 Capsules of 186 mg (Equivalent to 200 mg Isavuconazole) and Single Intravenous Solution Dose Administration of 372 mg (Equivalent to 200 mg Isavuconazole) via Nasogastric (NG) Tube in Healthy Adult Subjects Under Fasted Conditions
	CRESEMBA IV Solution via NG Tube		CRESEMBA Oral Capsules		NG Tube/Oral Capsule
Pharmacokinetic Parameter	N	Mean (%CV)	N	Mean (%CV)	GMR (90% CI)
C_max(mg/L)	13	2.3 (23.6)	13	2.2 (26.7)	105.34 (89-124)
AUC_0-72hr (mg·hr/L)	13	34.9 (22.1)	13	35.8 (24.6)	97.81 (93-103)
AUC_0-∞ (mg·hr/L)	12	98.1 (44.5)	12	100.1 (46.8)	99.27 (93-106)
GMR = Geometric least-squares mean ratio; CI = confidence interval

Effect of Food

Coadministration of CRESEMBA equivalent to isavuconazole 400 mg oral dose with a high-fat meal reduced isavuconazole C_maxby 9% and increased AUC by 9%. CRESEMBA can be taken with or without food.

Distribution

Elimination

Metabolism

in vitro

In vivo

studies indicate that CYP3A4, CYP3A5 and subsequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole.

Excretion

Renal excretion of isavuconazole itself was less than 1% of the dose administered.

Special populations

Geriatric Patients

Pediatric Patients

Table 8. Derived Steady State Isavuconazole AUC (mg•hr/L) values in Pediatric Patients, by Age Group
Dosage	15 mg/kg Estimated AUCss values of 15 mg/kg that were derived from existing values of pediatric patients that received 10 mg/kg of CRESEMBA for injection administered intravenously.	10 mg/kg CRESEMBA for injection administered intravenously.	10 mg/kg or Maximum Dose of 372 mg CRESEMBA for injection administered intravenously or CRESEMBA capsules administered orally.
Age Group	1 to < 3 years (n=5)	3 to < 6 years (n=10)	6 to < 12 years (n=29)	12 to < 18 years (n=29)
Mean	80.2	103.3	97.3	104.2
Median	64.3	110.3	87.7	97.7
Minimum - Maximum	53.7 - 155	51.5 – 159.1	37.8– 153.8	35.5 – 215.6

Race

Gender

AUC estimates were similar between young female and male subjects (18 years to 45 years). There was a difference in AUC for elderly females

(see

Geriatric

section above)

. No dose adjustment is required based on gender.

Patients with Renal Impairment

Isavuconazole is not readily dialyzable. A dose adjustment is not warranted in patients with ESRD.

Patients with Hepatic Impairment

Drug Interaction Studies

In Vitro Studies

CYP450 Enzymes:

Isavuconazole is a substrate of CYP3A4 and CYP3A5. Isavuconazole is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Isavuconazole is an inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9.

Transporter Systems:

Isavuconazole is an inhibitor of P-gp-, BCRP- and OCT2.

Clinical Studies and Model-Informed Approaches

The effects of ketoconazole, rifampin, lopinavir/ritonavir, and esomeprazole on isavuconazole are shown inFigure 1.

Ketoconazole:

Lopinavir/Ritonavir:

Rifampin:

Figure 1. The Effect of Coadministered Drugs on Isavuconazole Exposure

CYP3A4 Substrates:

CRESEMBA increased the systemic exposure of sensitive CYP3A4 substrates midazolam, sirolimus and tacrolimus approximately 2-fold, and therefore CRESEMBA is a moderate inhibitor of CYP3A4.

Figure 2. The Effect of Isavuconazole on Coadministered CYP3A4 Substrate Medications

The effects of isavuconazole on other CYP substrates: caffeine, bupropion, methadone, repaglinide, warfarin, omeprazole, and dextromethorphan, are shown inFigure 3.

Figure 3. The Effect of Isavuconazole on Exposure of Coadministered CYP Substrate Medications

The effects of isavuconazole on the substrates of UGT and transporters: mycophenolate mofetil (MMF), methotrexate, metformin, and digoxin are shown inFigure 4.

Figure 4. The Effect of Isavuconazole on Exposure on the Substrates of UGT and Transporters

Vincristine:

Vincristine (P-gp substrate) exposure is predicted to increase by less than 2-fold in pediatric and adult patients following concomitant administration with CRESEMBA.

(

12.3 Pharmacokinetics

General Pharmacokinetics

Table 6. Steady State Pharmacokinetic Parameters of Isavuconazole Following Administration of 186 mg CRESEMBA Capsules
Parameter	CRESEMBA 186 mg 2 Capsules Each capsule contains the equivalent of 100 mg of isavuconazole. (n = 37)	CRESEMBA 186 mg 6 Capsules (n = 32)
C_max(mg/L)
Mean SD CV %	7.5 1.9 25.2	20.0 3.6 17.9
t_max(hr)
Median Range	3.0 2.0 – 4.0	4.0 2.0 – 4.0
AUC (mg•hr/L)
Mean SD CV %	121.4 35.8 29.5	352.8 72.0 20.4

Absorption

CRESEMBA given orally as an intravenous solution administered via nasogastric (NG) tube provides systemic isavuconazole exposure that is similar to the oral capsule (Table 7).

Table 7. Statistical Comparison of Plasma Pharmacokinetics of Isavuconazole Following Single Oral Dose Administration of 2 Capsules of 186 mg (Equivalent to 200 mg Isavuconazole) and Single Intravenous Solution Dose Administration of 372 mg (Equivalent to 200 mg Isavuconazole) via Nasogastric (NG) Tube in Healthy Adult Subjects Under Fasted Conditions
	CRESEMBA IV Solution via NG Tube		CRESEMBA Oral Capsules		NG Tube/Oral Capsule
Pharmacokinetic Parameter	N	Mean (%CV)	N	Mean (%CV)	GMR (90% CI)
C_max(mg/L)	13	2.3 (23.6)	13	2.2 (26.7)	105.34 (89-124)
AUC_0-72hr (mg·hr/L)	13	34.9 (22.1)	13	35.8 (24.6)	97.81 (93-103)
AUC_0-∞ (mg·hr/L)	12	98.1 (44.5)	12	100.1 (46.8)	99.27 (93-106)
GMR = Geometric least-squares mean ratio; CI = confidence interval

Effect of Food

Coadministration of CRESEMBA equivalent to isavuconazole 400 mg oral dose with a high-fat meal reduced isavuconazole C_maxby 9% and increased AUC by 9%. CRESEMBA can be taken with or without food.

Distribution

Elimination

Metabolism

in vitro

In vivo

studies indicate that CYP3A4, CYP3A5 and subsequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole.

Excretion

Renal excretion of isavuconazole itself was less than 1% of the dose administered.

Special populations

Geriatric Patients

Pediatric Patients

Table 8. Derived Steady State Isavuconazole AUC (mg•hr/L) values in Pediatric Patients, by Age Group
Dosage	15 mg/kg Estimated AUCss values of 15 mg/kg that were derived from existing values of pediatric patients that received 10 mg/kg of CRESEMBA for injection administered intravenously.	10 mg/kg CRESEMBA for injection administered intravenously.	10 mg/kg or Maximum Dose of 372 mg CRESEMBA for injection administered intravenously or CRESEMBA capsules administered orally.
Age Group	1 to < 3 years (n=5)	3 to < 6 years (n=10)	6 to < 12 years (n=29)	12 to < 18 years (n=29)
Mean	80.2	103.3	97.3	104.2
Median	64.3	110.3	87.7	97.7
Minimum - Maximum	53.7 - 155	51.5 – 159.1	37.8– 153.8	35.5 – 215.6

Race

Gender

AUC estimates were similar between young female and male subjects (18 years to 45 years). There was a difference in AUC for elderly females

(see

Geriatric

section above)

. No dose adjustment is required based on gender.

Patients with Renal Impairment

Isavuconazole is not readily dialyzable. A dose adjustment is not warranted in patients with ESRD.

Patients with Hepatic Impairment

Drug Interaction Studies

In Vitro Studies

CYP450 Enzymes:

Isavuconazole is a substrate of CYP3A4 and CYP3A5. Isavuconazole is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Isavuconazole is an inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9.

Transporter Systems:

Isavuconazole is an inhibitor of P-gp-, BCRP- and OCT2.

Clinical Studies and Model-Informed Approaches

The effects of ketoconazole, rifampin, lopinavir/ritonavir, and esomeprazole on isavuconazole are shown inFigure 1.

Ketoconazole:

Lopinavir/Ritonavir:

Rifampin:

Figure 1. The Effect of Coadministered Drugs on Isavuconazole Exposure

CYP3A4 Substrates:

CRESEMBA increased the systemic exposure of sensitive CYP3A4 substrates midazolam, sirolimus and tacrolimus approximately 2-fold, and therefore CRESEMBA is a moderate inhibitor of CYP3A4.

Figure 2. The Effect of Isavuconazole on Coadministered CYP3A4 Substrate Medications

The effects of isavuconazole on other CYP substrates: caffeine, bupropion, methadone, repaglinide, warfarin, omeprazole, and dextromethorphan, are shown inFigure 3.

Figure 3. The Effect of Isavuconazole on Exposure of Coadministered CYP Substrate Medications

The effects of isavuconazole on the substrates of UGT and transporters: mycophenolate mofetil (MMF), methotrexate, metformin, and digoxin are shown inFigure 4.

Figure 4. The Effect of Isavuconazole on Exposure on the Substrates of UGT and Transporters

Vincristine:

Vincristine (P-gp substrate) exposure is predicted to increase by less than 2-fold in pediatric and adult patients following concomitant administration with CRESEMBA.

)]

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

12.3 Pharmacokinetics

General Pharmacokinetics

Table 6. Steady State Pharmacokinetic Parameters of Isavuconazole Following Administration of 186 mg CRESEMBA Capsules
Parameter	CRESEMBA 186 mg 2 Capsules Each capsule contains the equivalent of 100 mg of isavuconazole. (n = 37)	CRESEMBA 186 mg 6 Capsules (n = 32)
C_max(mg/L)
Mean SD CV %	7.5 1.9 25.2	20.0 3.6 17.9
t_max(hr)
Median Range	3.0 2.0 – 4.0	4.0 2.0 – 4.0
AUC (mg•hr/L)
Mean SD CV %	121.4 35.8 29.5	352.8 72.0 20.4

Absorption

CRESEMBA given orally as an intravenous solution administered via nasogastric (NG) tube provides systemic isavuconazole exposure that is similar to the oral capsule (Table 7).

Table 7. Statistical Comparison of Plasma Pharmacokinetics of Isavuconazole Following Single Oral Dose Administration of 2 Capsules of 186 mg (Equivalent to 200 mg Isavuconazole) and Single Intravenous Solution Dose Administration of 372 mg (Equivalent to 200 mg Isavuconazole) via Nasogastric (NG) Tube in Healthy Adult Subjects Under Fasted Conditions
	CRESEMBA IV Solution via NG Tube		CRESEMBA Oral Capsules		NG Tube/Oral Capsule
Pharmacokinetic Parameter	N	Mean (%CV)	N	Mean (%CV)	GMR (90% CI)
C_max(mg/L)	13	2.3 (23.6)	13	2.2 (26.7)	105.34 (89-124)
AUC_0-72hr (mg·hr/L)	13	34.9 (22.1)	13	35.8 (24.6)	97.81 (93-103)
AUC_0-∞ (mg·hr/L)	12	98.1 (44.5)	12	100.1 (46.8)	99.27 (93-106)
GMR = Geometric least-squares mean ratio; CI = confidence interval

Effect of Food

Coadministration of CRESEMBA equivalent to isavuconazole 400 mg oral dose with a high-fat meal reduced isavuconazole C_maxby 9% and increased AUC by 9%. CRESEMBA can be taken with or without food.

Distribution

Elimination

Metabolism

in vitro

In vivo

studies indicate that CYP3A4, CYP3A5 and subsequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole.

Excretion

Renal excretion of isavuconazole itself was less than 1% of the dose administered.

Special populations

Geriatric Patients

Pediatric Patients

Table 8. Derived Steady State Isavuconazole AUC (mg•hr/L) values in Pediatric Patients, by Age Group
Dosage	15 mg/kg Estimated AUCss values of 15 mg/kg that were derived from existing values of pediatric patients that received 10 mg/kg of CRESEMBA for injection administered intravenously.	10 mg/kg CRESEMBA for injection administered intravenously.	10 mg/kg or Maximum Dose of 372 mg CRESEMBA for injection administered intravenously or CRESEMBA capsules administered orally.
Age Group	1 to < 3 years (n=5)	3 to < 6 years (n=10)	6 to < 12 years (n=29)	12 to < 18 years (n=29)
Mean	80.2	103.3	97.3	104.2
Median	64.3	110.3	87.7	97.7
Minimum - Maximum	53.7 - 155	51.5 – 159.1	37.8– 153.8	35.5 – 215.6

Race

Gender

AUC estimates were similar between young female and male subjects (18 years to 45 years). There was a difference in AUC for elderly females

(see

Geriatric

section above)

. No dose adjustment is required based on gender.

Patients with Renal Impairment

Isavuconazole is not readily dialyzable. A dose adjustment is not warranted in patients with ESRD.

Patients with Hepatic Impairment

Drug Interaction Studies

In Vitro Studies

CYP450 Enzymes:

Isavuconazole is a substrate of CYP3A4 and CYP3A5. Isavuconazole is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Isavuconazole is an inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9.

Transporter Systems:

Isavuconazole is an inhibitor of P-gp-, BCRP- and OCT2.

Clinical Studies and Model-Informed Approaches

The effects of ketoconazole, rifampin, lopinavir/ritonavir, and esomeprazole on isavuconazole are shown inFigure 1.

Ketoconazole:

Lopinavir/Ritonavir:

Rifampin:

Figure 1. The Effect of Coadministered Drugs on Isavuconazole Exposure

CYP3A4 Substrates:

CRESEMBA increased the systemic exposure of sensitive CYP3A4 substrates midazolam, sirolimus and tacrolimus approximately 2-fold, and therefore CRESEMBA is a moderate inhibitor of CYP3A4.

Figure 2. The Effect of Isavuconazole on Coadministered CYP3A4 Substrate Medications

The effects of isavuconazole on other CYP substrates: caffeine, bupropion, methadone, repaglinide, warfarin, omeprazole, and dextromethorphan, are shown inFigure 3.

Figure 3. The Effect of Isavuconazole on Exposure of Coadministered CYP Substrate Medications

The effects of isavuconazole on the substrates of UGT and transporters: mycophenolate mofetil (MMF), methotrexate, metformin, and digoxin are shown inFigure 4.

Figure 4. The Effect of Isavuconazole on Exposure on the Substrates of UGT and Transporters

Vincristine:

Vincristine (P-gp substrate) exposure is predicted to increase by less than 2-fold in pediatric and adult patients following concomitant administration with CRESEMBA.

(

12.3 Pharmacokinetics

General Pharmacokinetics

Table 6. Steady State Pharmacokinetic Parameters of Isavuconazole Following Administration of 186 mg CRESEMBA Capsules
Parameter	CRESEMBA 186 mg 2 Capsules Each capsule contains the equivalent of 100 mg of isavuconazole. (n = 37)	CRESEMBA 186 mg 6 Capsules (n = 32)
C_max(mg/L)
Mean SD CV %	7.5 1.9 25.2	20.0 3.6 17.9
t_max(hr)
Median Range	3.0 2.0 – 4.0	4.0 2.0 – 4.0
AUC (mg•hr/L)
Mean SD CV %	121.4 35.8 29.5	352.8 72.0 20.4

Absorption

CRESEMBA given orally as an intravenous solution administered via nasogastric (NG) tube provides systemic isavuconazole exposure that is similar to the oral capsule (Table 7).

Table 7. Statistical Comparison of Plasma Pharmacokinetics of Isavuconazole Following Single Oral Dose Administration of 2 Capsules of 186 mg (Equivalent to 200 mg Isavuconazole) and Single Intravenous Solution Dose Administration of 372 mg (Equivalent to 200 mg Isavuconazole) via Nasogastric (NG) Tube in Healthy Adult Subjects Under Fasted Conditions
	CRESEMBA IV Solution via NG Tube		CRESEMBA Oral Capsules		NG Tube/Oral Capsule
Pharmacokinetic Parameter	N	Mean (%CV)	N	Mean (%CV)	GMR (90% CI)
C_max(mg/L)	13	2.3 (23.6)	13	2.2 (26.7)	105.34 (89-124)
AUC_0-72hr (mg·hr/L)	13	34.9 (22.1)	13	35.8 (24.6)	97.81 (93-103)
AUC_0-∞ (mg·hr/L)	12	98.1 (44.5)	12	100.1 (46.8)	99.27 (93-106)
GMR = Geometric least-squares mean ratio; CI = confidence interval

Effect of Food

Coadministration of CRESEMBA equivalent to isavuconazole 400 mg oral dose with a high-fat meal reduced isavuconazole C_maxby 9% and increased AUC by 9%. CRESEMBA can be taken with or without food.

Distribution

Elimination

Metabolism

in vitro

In vivo

studies indicate that CYP3A4, CYP3A5 and subsequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole.

Excretion

Renal excretion of isavuconazole itself was less than 1% of the dose administered.

Special populations

Geriatric Patients

Pediatric Patients

Table 8. Derived Steady State Isavuconazole AUC (mg•hr/L) values in Pediatric Patients, by Age Group
Dosage	15 mg/kg Estimated AUCss values of 15 mg/kg that were derived from existing values of pediatric patients that received 10 mg/kg of CRESEMBA for injection administered intravenously.	10 mg/kg CRESEMBA for injection administered intravenously.	10 mg/kg or Maximum Dose of 372 mg CRESEMBA for injection administered intravenously or CRESEMBA capsules administered orally.
Age Group	1 to < 3 years (n=5)	3 to < 6 years (n=10)	6 to < 12 years (n=29)	12 to < 18 years (n=29)
Mean	80.2	103.3	97.3	104.2
Median	64.3	110.3	87.7	97.7
Minimum - Maximum	53.7 - 155	51.5 – 159.1	37.8– 153.8	35.5 – 215.6

Race

Gender

AUC estimates were similar between young female and male subjects (18 years to 45 years). There was a difference in AUC for elderly females

(see

Geriatric

section above)

. No dose adjustment is required based on gender.

Patients with Renal Impairment

Isavuconazole is not readily dialyzable. A dose adjustment is not warranted in patients with ESRD.

Patients with Hepatic Impairment

Drug Interaction Studies

In Vitro Studies

CYP450 Enzymes:

Isavuconazole is a substrate of CYP3A4 and CYP3A5. Isavuconazole is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Isavuconazole is an inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9.

Transporter Systems:

Isavuconazole is an inhibitor of P-gp-, BCRP- and OCT2.

Clinical Studies and Model-Informed Approaches

The effects of ketoconazole, rifampin, lopinavir/ritonavir, and esomeprazole on isavuconazole are shown inFigure 1.

Ketoconazole:

Lopinavir/Ritonavir:

Rifampin:

Figure 1. The Effect of Coadministered Drugs on Isavuconazole Exposure

CYP3A4 Substrates:

CRESEMBA increased the systemic exposure of sensitive CYP3A4 substrates midazolam, sirolimus and tacrolimus approximately 2-fold, and therefore CRESEMBA is a moderate inhibitor of CYP3A4.

Figure 2. The Effect of Isavuconazole on Coadministered CYP3A4 Substrate Medications

The effects of isavuconazole on other CYP substrates: caffeine, bupropion, methadone, repaglinide, warfarin, omeprazole, and dextromethorphan, are shown inFigure 3.

Figure 3. The Effect of Isavuconazole on Exposure of Coadministered CYP Substrate Medications

The effects of isavuconazole on the substrates of UGT and transporters: mycophenolate mofetil (MMF), methotrexate, metformin, and digoxin are shown inFigure 4.

Figure 4. The Effect of Isavuconazole on Exposure on the Substrates of UGT and Transporters

Vincristine:

Vincristine (P-gp substrate) exposure is predicted to increase by less than 2-fold in pediatric and adult patients following concomitant administration with CRESEMBA.

)]

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

12.3 Pharmacokinetics

General Pharmacokinetics

Table 6. Steady State Pharmacokinetic Parameters of Isavuconazole Following Administration of 186 mg CRESEMBA Capsules
Parameter	CRESEMBA 186 mg 2 Capsules Each capsule contains the equivalent of 100 mg of isavuconazole. (n = 37)	CRESEMBA 186 mg 6 Capsules (n = 32)
C_max(mg/L)
Mean SD CV %	7.5 1.9 25.2	20.0 3.6 17.9
t_max(hr)
Median Range	3.0 2.0 – 4.0	4.0 2.0 – 4.0
AUC (mg•hr/L)
Mean SD CV %	121.4 35.8 29.5	352.8 72.0 20.4

Absorption

CRESEMBA given orally as an intravenous solution administered via nasogastric (NG) tube provides systemic isavuconazole exposure that is similar to the oral capsule (Table 7).

Table 7. Statistical Comparison of Plasma Pharmacokinetics of Isavuconazole Following Single Oral Dose Administration of 2 Capsules of 186 mg (Equivalent to 200 mg Isavuconazole) and Single Intravenous Solution Dose Administration of 372 mg (Equivalent to 200 mg Isavuconazole) via Nasogastric (NG) Tube in Healthy Adult Subjects Under Fasted Conditions
	CRESEMBA IV Solution via NG Tube		CRESEMBA Oral Capsules		NG Tube/Oral Capsule
Pharmacokinetic Parameter	N	Mean (%CV)	N	Mean (%CV)	GMR (90% CI)
C_max(mg/L)	13	2.3 (23.6)	13	2.2 (26.7)	105.34 (89-124)
AUC_0-72hr (mg·hr/L)	13	34.9 (22.1)	13	35.8 (24.6)	97.81 (93-103)
AUC_0-∞ (mg·hr/L)	12	98.1 (44.5)	12	100.1 (46.8)	99.27 (93-106)
GMR = Geometric least-squares mean ratio; CI = confidence interval

Effect of Food

Coadministration of CRESEMBA equivalent to isavuconazole 400 mg oral dose with a high-fat meal reduced isavuconazole C_maxby 9% and increased AUC by 9%. CRESEMBA can be taken with or without food.

Distribution

Elimination

Metabolism

in vitro

In vivo

studies indicate that CYP3A4, CYP3A5 and subsequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole.

Excretion

Renal excretion of isavuconazole itself was less than 1% of the dose administered.

Special populations

Geriatric Patients

Pediatric Patients

Table 8. Derived Steady State Isavuconazole AUC (mg•hr/L) values in Pediatric Patients, by Age Group
Dosage	15 mg/kg Estimated AUCss values of 15 mg/kg that were derived from existing values of pediatric patients that received 10 mg/kg of CRESEMBA for injection administered intravenously.	10 mg/kg CRESEMBA for injection administered intravenously.	10 mg/kg or Maximum Dose of 372 mg CRESEMBA for injection administered intravenously or CRESEMBA capsules administered orally.
Age Group	1 to < 3 years (n=5)	3 to < 6 years (n=10)	6 to < 12 years (n=29)	12 to < 18 years (n=29)
Mean	80.2	103.3	97.3	104.2
Median	64.3	110.3	87.7	97.7
Minimum - Maximum	53.7 - 155	51.5 – 159.1	37.8– 153.8	35.5 – 215.6

Race

Gender

AUC estimates were similar between young female and male subjects (18 years to 45 years). There was a difference in AUC for elderly females

(see

Geriatric

section above)

. No dose adjustment is required based on gender.

Patients with Renal Impairment

Isavuconazole is not readily dialyzable. A dose adjustment is not warranted in patients with ESRD.

Patients with Hepatic Impairment

Drug Interaction Studies

In Vitro Studies

CYP450 Enzymes:

Isavuconazole is a substrate of CYP3A4 and CYP3A5. Isavuconazole is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Isavuconazole is an inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9.

Transporter Systems:

Isavuconazole is an inhibitor of P-gp-, BCRP- and OCT2.

Clinical Studies and Model-Informed Approaches

The effects of ketoconazole, rifampin, lopinavir/ritonavir, and esomeprazole on isavuconazole are shown inFigure 1.

Ketoconazole:

Lopinavir/Ritonavir:

Rifampin:

Figure 1. The Effect of Coadministered Drugs on Isavuconazole Exposure

CYP3A4 Substrates:

CRESEMBA increased the systemic exposure of sensitive CYP3A4 substrates midazolam, sirolimus and tacrolimus approximately 2-fold, and therefore CRESEMBA is a moderate inhibitor of CYP3A4.

Figure 2. The Effect of Isavuconazole on Coadministered CYP3A4 Substrate Medications

The effects of isavuconazole on other CYP substrates: caffeine, bupropion, methadone, repaglinide, warfarin, omeprazole, and dextromethorphan, are shown inFigure 3.

Figure 3. The Effect of Isavuconazole on Exposure of Coadministered CYP Substrate Medications

The effects of isavuconazole on the substrates of UGT and transporters: mycophenolate mofetil (MMF), methotrexate, metformin, and digoxin are shown inFigure 4.

Figure 4. The Effect of Isavuconazole on Exposure on the Substrates of UGT and Transporters

Vincristine:

Vincristine (P-gp substrate) exposure is predicted to increase by less than 2-fold in pediatric and adult patients following concomitant administration with CRESEMBA.

(

12.3 Pharmacokinetics

General Pharmacokinetics

Table 6. Steady State Pharmacokinetic Parameters of Isavuconazole Following Administration of 186 mg CRESEMBA Capsules
Parameter	CRESEMBA 186 mg 2 Capsules Each capsule contains the equivalent of 100 mg of isavuconazole. (n = 37)	CRESEMBA 186 mg 6 Capsules (n = 32)
C_max(mg/L)
Mean SD CV %	7.5 1.9 25.2	20.0 3.6 17.9
t_max(hr)
Median Range	3.0 2.0 – 4.0	4.0 2.0 – 4.0
AUC (mg•hr/L)
Mean SD CV %	121.4 35.8 29.5	352.8 72.0 20.4

Absorption

CRESEMBA given orally as an intravenous solution administered via nasogastric (NG) tube provides systemic isavuconazole exposure that is similar to the oral capsule (Table 7).

Table 7. Statistical Comparison of Plasma Pharmacokinetics of Isavuconazole Following Single Oral Dose Administration of 2 Capsules of 186 mg (Equivalent to 200 mg Isavuconazole) and Single Intravenous Solution Dose Administration of 372 mg (Equivalent to 200 mg Isavuconazole) via Nasogastric (NG) Tube in Healthy Adult Subjects Under Fasted Conditions
	CRESEMBA IV Solution via NG Tube		CRESEMBA Oral Capsules		NG Tube/Oral Capsule
Pharmacokinetic Parameter	N	Mean (%CV)	N	Mean (%CV)	GMR (90% CI)
C_max(mg/L)	13	2.3 (23.6)	13	2.2 (26.7)	105.34 (89-124)
AUC_0-72hr (mg·hr/L)	13	34.9 (22.1)	13	35.8 (24.6)	97.81 (93-103)
AUC_0-∞ (mg·hr/L)	12	98.1 (44.5)	12	100.1 (46.8)	99.27 (93-106)
GMR = Geometric least-squares mean ratio; CI = confidence interval

Effect of Food

Coadministration of CRESEMBA equivalent to isavuconazole 400 mg oral dose with a high-fat meal reduced isavuconazole C_maxby 9% and increased AUC by 9%. CRESEMBA can be taken with or without food.

Distribution

Elimination

Metabolism

in vitro

In vivo

studies indicate that CYP3A4, CYP3A5 and subsequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole.

Excretion

Renal excretion of isavuconazole itself was less than 1% of the dose administered.

Special populations

Geriatric Patients

Pediatric Patients

Table 8. Derived Steady State Isavuconazole AUC (mg•hr/L) values in Pediatric Patients, by Age Group
Dosage	15 mg/kg Estimated AUCss values of 15 mg/kg that were derived from existing values of pediatric patients that received 10 mg/kg of CRESEMBA for injection administered intravenously.	10 mg/kg CRESEMBA for injection administered intravenously.	10 mg/kg or Maximum Dose of 372 mg CRESEMBA for injection administered intravenously or CRESEMBA capsules administered orally.
Age Group	1 to < 3 years (n=5)	3 to < 6 years (n=10)	6 to < 12 years (n=29)	12 to < 18 years (n=29)
Mean	80.2	103.3	97.3	104.2
Median	64.3	110.3	87.7	97.7
Minimum - Maximum	53.7 - 155	51.5 – 159.1	37.8– 153.8	35.5 – 215.6

Race

Gender

AUC estimates were similar between young female and male subjects (18 years to 45 years). There was a difference in AUC for elderly females

(see

Geriatric

section above)

. No dose adjustment is required based on gender.

Patients with Renal Impairment

Isavuconazole is not readily dialyzable. A dose adjustment is not warranted in patients with ESRD.

Patients with Hepatic Impairment

Drug Interaction Studies

In Vitro Studies

CYP450 Enzymes:

Isavuconazole is a substrate of CYP3A4 and CYP3A5. Isavuconazole is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Isavuconazole is an inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9.

Transporter Systems:

Isavuconazole is an inhibitor of P-gp-, BCRP- and OCT2.

Clinical Studies and Model-Informed Approaches

The effects of ketoconazole, rifampin, lopinavir/ritonavir, and esomeprazole on isavuconazole are shown inFigure 1.

Ketoconazole:

Lopinavir/Ritonavir:

Rifampin:

Figure 1. The Effect of Coadministered Drugs on Isavuconazole Exposure

CYP3A4 Substrates:

CRESEMBA increased the systemic exposure of sensitive CYP3A4 substrates midazolam, sirolimus and tacrolimus approximately 2-fold, and therefore CRESEMBA is a moderate inhibitor of CYP3A4.

Figure 2. The Effect of Isavuconazole on Coadministered CYP3A4 Substrate Medications

The effects of isavuconazole on other CYP substrates: caffeine, bupropion, methadone, repaglinide, warfarin, omeprazole, and dextromethorphan, are shown inFigure 3.

Figure 3. The Effect of Isavuconazole on Exposure of Coadministered CYP Substrate Medications

The effects of isavuconazole on the substrates of UGT and transporters: mycophenolate mofetil (MMF), methotrexate, metformin, and digoxin are shown inFigure 4.

Figure 4. The Effect of Isavuconazole on Exposure on the Substrates of UGT and Transporters

Vincristine:

Vincristine (P-gp substrate) exposure is predicted to increase by less than 2-fold in pediatric and adult patients following concomitant administration with CRESEMBA.

)]

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

12.3 Pharmacokinetics

General Pharmacokinetics

Table 6. Steady State Pharmacokinetic Parameters of Isavuconazole Following Administration of 186 mg CRESEMBA Capsules
Parameter	CRESEMBA 186 mg 2 Capsules Each capsule contains the equivalent of 100 mg of isavuconazole. (n = 37)	CRESEMBA 186 mg 6 Capsules (n = 32)
C_max(mg/L)
Mean SD CV %	7.5 1.9 25.2	20.0 3.6 17.9
t_max(hr)
Median Range	3.0 2.0 – 4.0	4.0 2.0 – 4.0
AUC (mg•hr/L)
Mean SD CV %	121.4 35.8 29.5	352.8 72.0 20.4

Absorption

CRESEMBA given orally as an intravenous solution administered via nasogastric (NG) tube provides systemic isavuconazole exposure that is similar to the oral capsule (Table 7).

Table 7. Statistical Comparison of Plasma Pharmacokinetics of Isavuconazole Following Single Oral Dose Administration of 2 Capsules of 186 mg (Equivalent to 200 mg Isavuconazole) and Single Intravenous Solution Dose Administration of 372 mg (Equivalent to 200 mg Isavuconazole) via Nasogastric (NG) Tube in Healthy Adult Subjects Under Fasted Conditions
	CRESEMBA IV Solution via NG Tube		CRESEMBA Oral Capsules		NG Tube/Oral Capsule
Pharmacokinetic Parameter	N	Mean (%CV)	N	Mean (%CV)	GMR (90% CI)
C_max(mg/L)	13	2.3 (23.6)	13	2.2 (26.7)	105.34 (89-124)
AUC_0-72hr (mg·hr/L)	13	34.9 (22.1)	13	35.8 (24.6)	97.81 (93-103)
AUC_0-∞ (mg·hr/L)	12	98.1 (44.5)	12	100.1 (46.8)	99.27 (93-106)
GMR = Geometric least-squares mean ratio; CI = confidence interval

Effect of Food

Coadministration of CRESEMBA equivalent to isavuconazole 400 mg oral dose with a high-fat meal reduced isavuconazole C_maxby 9% and increased AUC by 9%. CRESEMBA can be taken with or without food.

Distribution

Elimination

Metabolism

in vitro

In vivo

studies indicate that CYP3A4, CYP3A5 and subsequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole.

Excretion

Renal excretion of isavuconazole itself was less than 1% of the dose administered.

Special populations

Geriatric Patients

Pediatric Patients

Table 8. Derived Steady State Isavuconazole AUC (mg•hr/L) values in Pediatric Patients, by Age Group
Dosage	15 mg/kg Estimated AUCss values of 15 mg/kg that were derived from existing values of pediatric patients that received 10 mg/kg of CRESEMBA for injection administered intravenously.	10 mg/kg CRESEMBA for injection administered intravenously.	10 mg/kg or Maximum Dose of 372 mg CRESEMBA for injection administered intravenously or CRESEMBA capsules administered orally.
Age Group	1 to < 3 years (n=5)	3 to < 6 years (n=10)	6 to < 12 years (n=29)	12 to < 18 years (n=29)
Mean	80.2	103.3	97.3	104.2
Median	64.3	110.3	87.7	97.7
Minimum - Maximum	53.7 - 155	51.5 – 159.1	37.8– 153.8	35.5 – 215.6

Race

Gender

AUC estimates were similar between young female and male subjects (18 years to 45 years). There was a difference in AUC for elderly females

(see

Geriatric

section above)

. No dose adjustment is required based on gender.

Patients with Renal Impairment

Isavuconazole is not readily dialyzable. A dose adjustment is not warranted in patients with ESRD.

Patients with Hepatic Impairment

Drug Interaction Studies

In Vitro Studies

CYP450 Enzymes:

Isavuconazole is a substrate of CYP3A4 and CYP3A5. Isavuconazole is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Isavuconazole is an inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9.

Transporter Systems:

Isavuconazole is an inhibitor of P-gp-, BCRP- and OCT2.

Clinical Studies and Model-Informed Approaches

The effects of ketoconazole, rifampin, lopinavir/ritonavir, and esomeprazole on isavuconazole are shown inFigure 1.

Ketoconazole:

Lopinavir/Ritonavir:

Rifampin:

Figure 1. The Effect of Coadministered Drugs on Isavuconazole Exposure

CYP3A4 Substrates:

CRESEMBA increased the systemic exposure of sensitive CYP3A4 substrates midazolam, sirolimus and tacrolimus approximately 2-fold, and therefore CRESEMBA is a moderate inhibitor of CYP3A4.

Figure 2. The Effect of Isavuconazole on Coadministered CYP3A4 Substrate Medications

The effects of isavuconazole on other CYP substrates: caffeine, bupropion, methadone, repaglinide, warfarin, omeprazole, and dextromethorphan, are shown inFigure 3.

Figure 3. The Effect of Isavuconazole on Exposure of Coadministered CYP Substrate Medications

The effects of isavuconazole on the substrates of UGT and transporters: mycophenolate mofetil (MMF), methotrexate, metformin, and digoxin are shown inFigure 4.

Figure 4. The Effect of Isavuconazole on Exposure on the Substrates of UGT and Transporters

Vincristine:

Vincristine (P-gp substrate) exposure is predicted to increase by less than 2-fold in pediatric and adult patients following concomitant administration with CRESEMBA.

(

12.3 Pharmacokinetics

General Pharmacokinetics

Table 6. Steady State Pharmacokinetic Parameters of Isavuconazole Following Administration of 186 mg CRESEMBA Capsules
Parameter	CRESEMBA 186 mg 2 Capsules Each capsule contains the equivalent of 100 mg of isavuconazole. (n = 37)	CRESEMBA 186 mg 6 Capsules (n = 32)
C_max(mg/L)
Mean SD CV %	7.5 1.9 25.2	20.0 3.6 17.9
t_max(hr)
Median Range	3.0 2.0 – 4.0	4.0 2.0 – 4.0
AUC (mg•hr/L)
Mean SD CV %	121.4 35.8 29.5	352.8 72.0 20.4

Absorption

CRESEMBA given orally as an intravenous solution administered via nasogastric (NG) tube provides systemic isavuconazole exposure that is similar to the oral capsule (Table 7).

Table 7. Statistical Comparison of Plasma Pharmacokinetics of Isavuconazole Following Single Oral Dose Administration of 2 Capsules of 186 mg (Equivalent to 200 mg Isavuconazole) and Single Intravenous Solution Dose Administration of 372 mg (Equivalent to 200 mg Isavuconazole) via Nasogastric (NG) Tube in Healthy Adult Subjects Under Fasted Conditions
	CRESEMBA IV Solution via NG Tube		CRESEMBA Oral Capsules		NG Tube/Oral Capsule
Pharmacokinetic Parameter	N	Mean (%CV)	N	Mean (%CV)	GMR (90% CI)
C_max(mg/L)	13	2.3 (23.6)	13	2.2 (26.7)	105.34 (89-124)
AUC_0-72hr (mg·hr/L)	13	34.9 (22.1)	13	35.8 (24.6)	97.81 (93-103)
AUC_0-∞ (mg·hr/L)	12	98.1 (44.5)	12	100.1 (46.8)	99.27 (93-106)
GMR = Geometric least-squares mean ratio; CI = confidence interval

Effect of Food

Coadministration of CRESEMBA equivalent to isavuconazole 400 mg oral dose with a high-fat meal reduced isavuconazole C_maxby 9% and increased AUC by 9%. CRESEMBA can be taken with or without food.

Distribution

Elimination

Metabolism

in vitro

In vivo

studies indicate that CYP3A4, CYP3A5 and subsequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole.

Excretion

Renal excretion of isavuconazole itself was less than 1% of the dose administered.

Special populations

Geriatric Patients

Pediatric Patients

Table 8. Derived Steady State Isavuconazole AUC (mg•hr/L) values in Pediatric Patients, by Age Group
Dosage	15 mg/kg Estimated AUCss values of 15 mg/kg that were derived from existing values of pediatric patients that received 10 mg/kg of CRESEMBA for injection administered intravenously.	10 mg/kg CRESEMBA for injection administered intravenously.	10 mg/kg or Maximum Dose of 372 mg CRESEMBA for injection administered intravenously or CRESEMBA capsules administered orally.
Age Group	1 to < 3 years (n=5)	3 to < 6 years (n=10)	6 to < 12 years (n=29)	12 to < 18 years (n=29)
Mean	80.2	103.3	97.3	104.2
Median	64.3	110.3	87.7	97.7
Minimum - Maximum	53.7 - 155	51.5 – 159.1	37.8– 153.8	35.5 – 215.6

Race

Gender

AUC estimates were similar between young female and male subjects (18 years to 45 years). There was a difference in AUC for elderly females

(see

Geriatric

section above)

. No dose adjustment is required based on gender.

Patients with Renal Impairment

Isavuconazole is not readily dialyzable. A dose adjustment is not warranted in patients with ESRD.

Patients with Hepatic Impairment

Drug Interaction Studies

In Vitro Studies

CYP450 Enzymes:

Isavuconazole is a substrate of CYP3A4 and CYP3A5. Isavuconazole is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Isavuconazole is an inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9.

Transporter Systems:

Isavuconazole is an inhibitor of P-gp-, BCRP- and OCT2.

Clinical Studies and Model-Informed Approaches

The effects of ketoconazole, rifampin, lopinavir/ritonavir, and esomeprazole on isavuconazole are shown inFigure 1.

Ketoconazole:

Lopinavir/Ritonavir:

Rifampin:

Figure 1. The Effect of Coadministered Drugs on Isavuconazole Exposure

CYP3A4 Substrates:

CRESEMBA increased the systemic exposure of sensitive CYP3A4 substrates midazolam, sirolimus and tacrolimus approximately 2-fold, and therefore CRESEMBA is a moderate inhibitor of CYP3A4.

Figure 2. The Effect of Isavuconazole on Coadministered CYP3A4 Substrate Medications

The effects of isavuconazole on other CYP substrates: caffeine, bupropion, methadone, repaglinide, warfarin, omeprazole, and dextromethorphan, are shown inFigure 3.

Figure 3. The Effect of Isavuconazole on Exposure of Coadministered CYP Substrate Medications

The effects of isavuconazole on the substrates of UGT and transporters: mycophenolate mofetil (MMF), methotrexate, metformin, and digoxin are shown inFigure 4.

Figure 4. The Effect of Isavuconazole on Exposure on the Substrates of UGT and Transporters

Vincristine:

Vincristine (P-gp substrate) exposure is predicted to increase by less than 2-fold in pediatric and adult patients following concomitant administration with CRESEMBA.

)]

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

12.3 Pharmacokinetics

General Pharmacokinetics

Table 6. Steady State Pharmacokinetic Parameters of Isavuconazole Following Administration of 186 mg CRESEMBA Capsules
Parameter	CRESEMBA 186 mg 2 Capsules Each capsule contains the equivalent of 100 mg of isavuconazole. (n = 37)	CRESEMBA 186 mg 6 Capsules (n = 32)
C_max(mg/L)
Mean SD CV %	7.5 1.9 25.2	20.0 3.6 17.9
t_max(hr)
Median Range	3.0 2.0 – 4.0	4.0 2.0 – 4.0
AUC (mg•hr/L)
Mean SD CV %	121.4 35.8 29.5	352.8 72.0 20.4

Absorption

CRESEMBA given orally as an intravenous solution administered via nasogastric (NG) tube provides systemic isavuconazole exposure that is similar to the oral capsule (Table 7).

Table 7. Statistical Comparison of Plasma Pharmacokinetics of Isavuconazole Following Single Oral Dose Administration of 2 Capsules of 186 mg (Equivalent to 200 mg Isavuconazole) and Single Intravenous Solution Dose Administration of 372 mg (Equivalent to 200 mg Isavuconazole) via Nasogastric (NG) Tube in Healthy Adult Subjects Under Fasted Conditions
	CRESEMBA IV Solution via NG Tube		CRESEMBA Oral Capsules		NG Tube/Oral Capsule
Pharmacokinetic Parameter	N	Mean (%CV)	N	Mean (%CV)	GMR (90% CI)
C_max(mg/L)	13	2.3 (23.6)	13	2.2 (26.7)	105.34 (89-124)
AUC_0-72hr (mg·hr/L)	13	34.9 (22.1)	13	35.8 (24.6)	97.81 (93-103)
AUC_0-∞ (mg·hr/L)	12	98.1 (44.5)	12	100.1 (46.8)	99.27 (93-106)
GMR = Geometric least-squares mean ratio; CI = confidence interval

Effect of Food

Coadministration of CRESEMBA equivalent to isavuconazole 400 mg oral dose with a high-fat meal reduced isavuconazole C_maxby 9% and increased AUC by 9%. CRESEMBA can be taken with or without food.

Distribution

Elimination

Metabolism

in vitro

In vivo

studies indicate that CYP3A4, CYP3A5 and subsequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole.

Excretion

Renal excretion of isavuconazole itself was less than 1% of the dose administered.

Special populations

Geriatric Patients

Pediatric Patients

Table 8. Derived Steady State Isavuconazole AUC (mg•hr/L) values in Pediatric Patients, by Age Group
Dosage	15 mg/kg Estimated AUCss values of 15 mg/kg that were derived from existing values of pediatric patients that received 10 mg/kg of CRESEMBA for injection administered intravenously.	10 mg/kg CRESEMBA for injection administered intravenously.	10 mg/kg or Maximum Dose of 372 mg CRESEMBA for injection administered intravenously or CRESEMBA capsules administered orally.
Age Group	1 to < 3 years (n=5)	3 to < 6 years (n=10)	6 to < 12 years (n=29)	12 to < 18 years (n=29)
Mean	80.2	103.3	97.3	104.2
Median	64.3	110.3	87.7	97.7
Minimum - Maximum	53.7 - 155	51.5 – 159.1	37.8– 153.8	35.5 – 215.6

Race

Gender

AUC estimates were similar between young female and male subjects (18 years to 45 years). There was a difference in AUC for elderly females

(see

Geriatric

section above)

. No dose adjustment is required based on gender.

Patients with Renal Impairment

Isavuconazole is not readily dialyzable. A dose adjustment is not warranted in patients with ESRD.

Patients with Hepatic Impairment

Drug Interaction Studies

In Vitro Studies

CYP450 Enzymes:

Isavuconazole is a substrate of CYP3A4 and CYP3A5. Isavuconazole is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Isavuconazole is an inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9.

Transporter Systems:

Isavuconazole is an inhibitor of P-gp-, BCRP- and OCT2.

Clinical Studies and Model-Informed Approaches

The effects of ketoconazole, rifampin, lopinavir/ritonavir, and esomeprazole on isavuconazole are shown inFigure 1.

Ketoconazole:

Lopinavir/Ritonavir:

Rifampin:

Figure 1. The Effect of Coadministered Drugs on Isavuconazole Exposure

CYP3A4 Substrates:

CRESEMBA increased the systemic exposure of sensitive CYP3A4 substrates midazolam, sirolimus and tacrolimus approximately 2-fold, and therefore CRESEMBA is a moderate inhibitor of CYP3A4.

Figure 2. The Effect of Isavuconazole on Coadministered CYP3A4 Substrate Medications

The effects of isavuconazole on other CYP substrates: caffeine, bupropion, methadone, repaglinide, warfarin, omeprazole, and dextromethorphan, are shown inFigure 3.

Figure 3. The Effect of Isavuconazole on Exposure of Coadministered CYP Substrate Medications

The effects of isavuconazole on the substrates of UGT and transporters: mycophenolate mofetil (MMF), methotrexate, metformin, and digoxin are shown inFigure 4.

Figure 4. The Effect of Isavuconazole on Exposure on the Substrates of UGT and Transporters

Vincristine:

Vincristine (P-gp substrate) exposure is predicted to increase by less than 2-fold in pediatric and adult patients following concomitant administration with CRESEMBA.

(

12.3 Pharmacokinetics

General Pharmacokinetics

Table 6. Steady State Pharmacokinetic Parameters of Isavuconazole Following Administration of 186 mg CRESEMBA Capsules
Parameter	CRESEMBA 186 mg 2 Capsules Each capsule contains the equivalent of 100 mg of isavuconazole. (n = 37)	CRESEMBA 186 mg 6 Capsules (n = 32)
C_max(mg/L)
Mean SD CV %	7.5 1.9 25.2	20.0 3.6 17.9
t_max(hr)
Median Range	3.0 2.0 – 4.0	4.0 2.0 – 4.0
AUC (mg•hr/L)
Mean SD CV %	121.4 35.8 29.5	352.8 72.0 20.4

Absorption

CRESEMBA given orally as an intravenous solution administered via nasogastric (NG) tube provides systemic isavuconazole exposure that is similar to the oral capsule (Table 7).

Table 7. Statistical Comparison of Plasma Pharmacokinetics of Isavuconazole Following Single Oral Dose Administration of 2 Capsules of 186 mg (Equivalent to 200 mg Isavuconazole) and Single Intravenous Solution Dose Administration of 372 mg (Equivalent to 200 mg Isavuconazole) via Nasogastric (NG) Tube in Healthy Adult Subjects Under Fasted Conditions
	CRESEMBA IV Solution via NG Tube		CRESEMBA Oral Capsules		NG Tube/Oral Capsule
Pharmacokinetic Parameter	N	Mean (%CV)	N	Mean (%CV)	GMR (90% CI)
C_max(mg/L)	13	2.3 (23.6)	13	2.2 (26.7)	105.34 (89-124)
AUC_0-72hr (mg·hr/L)	13	34.9 (22.1)	13	35.8 (24.6)	97.81 (93-103)
AUC_0-∞ (mg·hr/L)	12	98.1 (44.5)	12	100.1 (46.8)	99.27 (93-106)
GMR = Geometric least-squares mean ratio; CI = confidence interval

Effect of Food

Coadministration of CRESEMBA equivalent to isavuconazole 400 mg oral dose with a high-fat meal reduced isavuconazole C_maxby 9% and increased AUC by 9%. CRESEMBA can be taken with or without food.

Distribution

Elimination

Metabolism

in vitro

In vivo

studies indicate that CYP3A4, CYP3A5 and subsequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole.

Excretion

Renal excretion of isavuconazole itself was less than 1% of the dose administered.

Special populations

Geriatric Patients

Pediatric Patients

Table 8. Derived Steady State Isavuconazole AUC (mg•hr/L) values in Pediatric Patients, by Age Group
Dosage	15 mg/kg Estimated AUCss values of 15 mg/kg that were derived from existing values of pediatric patients that received 10 mg/kg of CRESEMBA for injection administered intravenously.	10 mg/kg CRESEMBA for injection administered intravenously.	10 mg/kg or Maximum Dose of 372 mg CRESEMBA for injection administered intravenously or CRESEMBA capsules administered orally.
Age Group	1 to < 3 years (n=5)	3 to < 6 years (n=10)	6 to < 12 years (n=29)	12 to < 18 years (n=29)
Mean	80.2	103.3	97.3	104.2
Median	64.3	110.3	87.7	97.7
Minimum - Maximum	53.7 - 155	51.5 – 159.1	37.8– 153.8	35.5 – 215.6

Race

Gender

AUC estimates were similar between young female and male subjects (18 years to 45 years). There was a difference in AUC for elderly females

(see

Geriatric

section above)

. No dose adjustment is required based on gender.

Patients with Renal Impairment

Isavuconazole is not readily dialyzable. A dose adjustment is not warranted in patients with ESRD.

Patients with Hepatic Impairment

Drug Interaction Studies

In Vitro Studies

CYP450 Enzymes:

Isavuconazole is a substrate of CYP3A4 and CYP3A5. Isavuconazole is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Isavuconazole is an inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9.

Transporter Systems:

Isavuconazole is an inhibitor of P-gp-, BCRP- and OCT2.

Clinical Studies and Model-Informed Approaches

The effects of ketoconazole, rifampin, lopinavir/ritonavir, and esomeprazole on isavuconazole are shown inFigure 1.

Ketoconazole:

Lopinavir/Ritonavir:

Rifampin:

Figure 1. The Effect of Coadministered Drugs on Isavuconazole Exposure

CYP3A4 Substrates:

CRESEMBA increased the systemic exposure of sensitive CYP3A4 substrates midazolam, sirolimus and tacrolimus approximately 2-fold, and therefore CRESEMBA is a moderate inhibitor of CYP3A4.

Figure 2. The Effect of Isavuconazole on Coadministered CYP3A4 Substrate Medications

The effects of isavuconazole on other CYP substrates: caffeine, bupropion, methadone, repaglinide, warfarin, omeprazole, and dextromethorphan, are shown inFigure 3.

Figure 3. The Effect of Isavuconazole on Exposure of Coadministered CYP Substrate Medications

The effects of isavuconazole on the substrates of UGT and transporters: mycophenolate mofetil (MMF), methotrexate, metformin, and digoxin are shown inFigure 4.

Figure 4. The Effect of Isavuconazole on Exposure on the Substrates of UGT and Transporters

Vincristine:

Vincristine (P-gp substrate) exposure is predicted to increase by less than 2-fold in pediatric and adult patients following concomitant administration with CRESEMBA.

)]

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

12.3 Pharmacokinetics

General Pharmacokinetics

Table 6. Steady State Pharmacokinetic Parameters of Isavuconazole Following Administration of 186 mg CRESEMBA Capsules
Parameter	CRESEMBA 186 mg 2 Capsules Each capsule contains the equivalent of 100 mg of isavuconazole. (n = 37)	CRESEMBA 186 mg 6 Capsules (n = 32)
C_max(mg/L)
Mean SD CV %	7.5 1.9 25.2	20.0 3.6 17.9
t_max(hr)
Median Range	3.0 2.0 – 4.0	4.0 2.0 – 4.0
AUC (mg•hr/L)
Mean SD CV %	121.4 35.8 29.5	352.8 72.0 20.4

Absorption

CRESEMBA given orally as an intravenous solution administered via nasogastric (NG) tube provides systemic isavuconazole exposure that is similar to the oral capsule (Table 7).

Table 7. Statistical Comparison of Plasma Pharmacokinetics of Isavuconazole Following Single Oral Dose Administration of 2 Capsules of 186 mg (Equivalent to 200 mg Isavuconazole) and Single Intravenous Solution Dose Administration of 372 mg (Equivalent to 200 mg Isavuconazole) via Nasogastric (NG) Tube in Healthy Adult Subjects Under Fasted Conditions
	CRESEMBA IV Solution via NG Tube		CRESEMBA Oral Capsules		NG Tube/Oral Capsule
Pharmacokinetic Parameter	N	Mean (%CV)	N	Mean (%CV)	GMR (90% CI)
C_max(mg/L)	13	2.3 (23.6)	13	2.2 (26.7)	105.34 (89-124)
AUC_0-72hr (mg·hr/L)	13	34.9 (22.1)	13	35.8 (24.6)	97.81 (93-103)
AUC_0-∞ (mg·hr/L)	12	98.1 (44.5)	12	100.1 (46.8)	99.27 (93-106)
GMR = Geometric least-squares mean ratio; CI = confidence interval

Effect of Food

Coadministration of CRESEMBA equivalent to isavuconazole 400 mg oral dose with a high-fat meal reduced isavuconazole C_maxby 9% and increased AUC by 9%. CRESEMBA can be taken with or without food.

Distribution

Elimination

Metabolism

in vitro

In vivo

studies indicate that CYP3A4, CYP3A5 and subsequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole.

Excretion

Renal excretion of isavuconazole itself was less than 1% of the dose administered.

Special populations

Geriatric Patients

Pediatric Patients

Table 8. Derived Steady State Isavuconazole AUC (mg•hr/L) values in Pediatric Patients, by Age Group
Dosage	15 mg/kg Estimated AUCss values of 15 mg/kg that were derived from existing values of pediatric patients that received 10 mg/kg of CRESEMBA for injection administered intravenously.	10 mg/kg CRESEMBA for injection administered intravenously.	10 mg/kg or Maximum Dose of 372 mg CRESEMBA for injection administered intravenously or CRESEMBA capsules administered orally.
Age Group	1 to < 3 years (n=5)	3 to < 6 years (n=10)	6 to < 12 years (n=29)	12 to < 18 years (n=29)
Mean	80.2	103.3	97.3	104.2
Median	64.3	110.3	87.7	97.7
Minimum - Maximum	53.7 - 155	51.5 – 159.1	37.8– 153.8	35.5 – 215.6

Race

Gender

AUC estimates were similar between young female and male subjects (18 years to 45 years). There was a difference in AUC for elderly females

(see

Geriatric

section above)

. No dose adjustment is required based on gender.

Patients with Renal Impairment

Isavuconazole is not readily dialyzable. A dose adjustment is not warranted in patients with ESRD.

Patients with Hepatic Impairment

Drug Interaction Studies

In Vitro Studies

CYP450 Enzymes:

Isavuconazole is a substrate of CYP3A4 and CYP3A5. Isavuconazole is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Isavuconazole is an inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9.

Transporter Systems:

Isavuconazole is an inhibitor of P-gp-, BCRP- and OCT2.

Clinical Studies and Model-Informed Approaches

The effects of ketoconazole, rifampin, lopinavir/ritonavir, and esomeprazole on isavuconazole are shown inFigure 1.

Ketoconazole:

Lopinavir/Ritonavir:

Rifampin:

Figure 1. The Effect of Coadministered Drugs on Isavuconazole Exposure

CYP3A4 Substrates:

CRESEMBA increased the systemic exposure of sensitive CYP3A4 substrates midazolam, sirolimus and tacrolimus approximately 2-fold, and therefore CRESEMBA is a moderate inhibitor of CYP3A4.

Figure 2. The Effect of Isavuconazole on Coadministered CYP3A4 Substrate Medications

The effects of isavuconazole on other CYP substrates: caffeine, bupropion, methadone, repaglinide, warfarin, omeprazole, and dextromethorphan, are shown inFigure 3.

Figure 3. The Effect of Isavuconazole on Exposure of Coadministered CYP Substrate Medications

The effects of isavuconazole on the substrates of UGT and transporters: mycophenolate mofetil (MMF), methotrexate, metformin, and digoxin are shown inFigure 4.

Figure 4. The Effect of Isavuconazole on Exposure on the Substrates of UGT and Transporters

Vincristine:

Vincristine (P-gp substrate) exposure is predicted to increase by less than 2-fold in pediatric and adult patients following concomitant administration with CRESEMBA.

(

12.3 Pharmacokinetics

General Pharmacokinetics

Table 6. Steady State Pharmacokinetic Parameters of Isavuconazole Following Administration of 186 mg CRESEMBA Capsules
Parameter	CRESEMBA 186 mg 2 Capsules Each capsule contains the equivalent of 100 mg of isavuconazole. (n = 37)	CRESEMBA 186 mg 6 Capsules (n = 32)
C_max(mg/L)
Mean SD CV %	7.5 1.9 25.2	20.0 3.6 17.9
t_max(hr)
Median Range	3.0 2.0 – 4.0	4.0 2.0 – 4.0
AUC (mg•hr/L)
Mean SD CV %	121.4 35.8 29.5	352.8 72.0 20.4

Absorption

CRESEMBA given orally as an intravenous solution administered via nasogastric (NG) tube provides systemic isavuconazole exposure that is similar to the oral capsule (Table 7).

Table 7. Statistical Comparison of Plasma Pharmacokinetics of Isavuconazole Following Single Oral Dose Administration of 2 Capsules of 186 mg (Equivalent to 200 mg Isavuconazole) and Single Intravenous Solution Dose Administration of 372 mg (Equivalent to 200 mg Isavuconazole) via Nasogastric (NG) Tube in Healthy Adult Subjects Under Fasted Conditions
	CRESEMBA IV Solution via NG Tube		CRESEMBA Oral Capsules		NG Tube/Oral Capsule
Pharmacokinetic Parameter	N	Mean (%CV)	N	Mean (%CV)	GMR (90% CI)
C_max(mg/L)	13	2.3 (23.6)	13	2.2 (26.7)	105.34 (89-124)
AUC_0-72hr (mg·hr/L)	13	34.9 (22.1)	13	35.8 (24.6)	97.81 (93-103)
AUC_0-∞ (mg·hr/L)	12	98.1 (44.5)	12	100.1 (46.8)	99.27 (93-106)
GMR = Geometric least-squares mean ratio; CI = confidence interval

Effect of Food

Coadministration of CRESEMBA equivalent to isavuconazole 400 mg oral dose with a high-fat meal reduced isavuconazole C_maxby 9% and increased AUC by 9%. CRESEMBA can be taken with or without food.

Distribution

Elimination

Metabolism

in vitro

In vivo

studies indicate that CYP3A4, CYP3A5 and subsequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole.

Excretion

Renal excretion of isavuconazole itself was less than 1% of the dose administered.

Special populations

Geriatric Patients

Pediatric Patients

Table 8. Derived Steady State Isavuconazole AUC (mg•hr/L) values in Pediatric Patients, by Age Group
Dosage	15 mg/kg Estimated AUCss values of 15 mg/kg that were derived from existing values of pediatric patients that received 10 mg/kg of CRESEMBA for injection administered intravenously.	10 mg/kg CRESEMBA for injection administered intravenously.	10 mg/kg or Maximum Dose of 372 mg CRESEMBA for injection administered intravenously or CRESEMBA capsules administered orally.
Age Group	1 to < 3 years (n=5)	3 to < 6 years (n=10)	6 to < 12 years (n=29)	12 to < 18 years (n=29)
Mean	80.2	103.3	97.3	104.2
Median	64.3	110.3	87.7	97.7
Minimum - Maximum	53.7 - 155	51.5 – 159.1	37.8– 153.8	35.5 – 215.6

Race

Gender

AUC estimates were similar between young female and male subjects (18 years to 45 years). There was a difference in AUC for elderly females

(see

Geriatric

section above)

. No dose adjustment is required based on gender.

Patients with Renal Impairment

Isavuconazole is not readily dialyzable. A dose adjustment is not warranted in patients with ESRD.

Patients with Hepatic Impairment

Drug Interaction Studies

In Vitro Studies

CYP450 Enzymes:

Isavuconazole is a substrate of CYP3A4 and CYP3A5. Isavuconazole is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Isavuconazole is an inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9.

Transporter Systems:

Isavuconazole is an inhibitor of P-gp-, BCRP- and OCT2.

Clinical Studies and Model-Informed Approaches

The effects of ketoconazole, rifampin, lopinavir/ritonavir, and esomeprazole on isavuconazole are shown inFigure 1.

Ketoconazole:

Lopinavir/Ritonavir:

Rifampin:

Figure 1. The Effect of Coadministered Drugs on Isavuconazole Exposure

CYP3A4 Substrates:

CRESEMBA increased the systemic exposure of sensitive CYP3A4 substrates midazolam, sirolimus and tacrolimus approximately 2-fold, and therefore CRESEMBA is a moderate inhibitor of CYP3A4.

Figure 2. The Effect of Isavuconazole on Coadministered CYP3A4 Substrate Medications

The effects of isavuconazole on other CYP substrates: caffeine, bupropion, methadone, repaglinide, warfarin, omeprazole, and dextromethorphan, are shown inFigure 3.

Figure 3. The Effect of Isavuconazole on Exposure of Coadministered CYP Substrate Medications

The effects of isavuconazole on the substrates of UGT and transporters: mycophenolate mofetil (MMF), methotrexate, metformin, and digoxin are shown inFigure 4.

Figure 4. The Effect of Isavuconazole on Exposure on the Substrates of UGT and Transporters

Vincristine:

Vincristine (P-gp substrate) exposure is predicted to increase by less than 2-fold in pediatric and adult patients following concomitant administration with CRESEMBA.

)]

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

12.3 Pharmacokinetics

General Pharmacokinetics

Table 6. Steady State Pharmacokinetic Parameters of Isavuconazole Following Administration of 186 mg CRESEMBA Capsules
Parameter	CRESEMBA 186 mg 2 Capsules Each capsule contains the equivalent of 100 mg of isavuconazole. (n = 37)	CRESEMBA 186 mg 6 Capsules (n = 32)
C_max(mg/L)
Mean SD CV %	7.5 1.9 25.2	20.0 3.6 17.9
t_max(hr)
Median Range	3.0 2.0 – 4.0	4.0 2.0 – 4.0
AUC (mg•hr/L)
Mean SD CV %	121.4 35.8 29.5	352.8 72.0 20.4

Absorption

CRESEMBA given orally as an intravenous solution administered via nasogastric (NG) tube provides systemic isavuconazole exposure that is similar to the oral capsule (Table 7).

Table 7. Statistical Comparison of Plasma Pharmacokinetics of Isavuconazole Following Single Oral Dose Administration of 2 Capsules of 186 mg (Equivalent to 200 mg Isavuconazole) and Single Intravenous Solution Dose Administration of 372 mg (Equivalent to 200 mg Isavuconazole) via Nasogastric (NG) Tube in Healthy Adult Subjects Under Fasted Conditions
	CRESEMBA IV Solution via NG Tube		CRESEMBA Oral Capsules		NG Tube/Oral Capsule
Pharmacokinetic Parameter	N	Mean (%CV)	N	Mean (%CV)	GMR (90% CI)
C_max(mg/L)	13	2.3 (23.6)	13	2.2 (26.7)	105.34 (89-124)
AUC_0-72hr (mg·hr/L)	13	34.9 (22.1)	13	35.8 (24.6)	97.81 (93-103)
AUC_0-∞ (mg·hr/L)	12	98.1 (44.5)	12	100.1 (46.8)	99.27 (93-106)
GMR = Geometric least-squares mean ratio; CI = confidence interval

Effect of Food

Coadministration of CRESEMBA equivalent to isavuconazole 400 mg oral dose with a high-fat meal reduced isavuconazole C_maxby 9% and increased AUC by 9%. CRESEMBA can be taken with or without food.

Distribution

Elimination

Metabolism

in vitro

In vivo

studies indicate that CYP3A4, CYP3A5 and subsequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole.

Excretion

Renal excretion of isavuconazole itself was less than 1% of the dose administered.

Special populations

Geriatric Patients

Pediatric Patients

Table 8. Derived Steady State Isavuconazole AUC (mg•hr/L) values in Pediatric Patients, by Age Group
Dosage	15 mg/kg Estimated AUCss values of 15 mg/kg that were derived from existing values of pediatric patients that received 10 mg/kg of CRESEMBA for injection administered intravenously.	10 mg/kg CRESEMBA for injection administered intravenously.	10 mg/kg or Maximum Dose of 372 mg CRESEMBA for injection administered intravenously or CRESEMBA capsules administered orally.
Age Group	1 to < 3 years (n=5)	3 to < 6 years (n=10)	6 to < 12 years (n=29)	12 to < 18 years (n=29)
Mean	80.2	103.3	97.3	104.2
Median	64.3	110.3	87.7	97.7
Minimum - Maximum	53.7 - 155	51.5 – 159.1	37.8– 153.8	35.5 – 215.6

Race

Gender

AUC estimates were similar between young female and male subjects (18 years to 45 years). There was a difference in AUC for elderly females

(see

Geriatric

section above)

. No dose adjustment is required based on gender.

Patients with Renal Impairment

Isavuconazole is not readily dialyzable. A dose adjustment is not warranted in patients with ESRD.

Patients with Hepatic Impairment

Drug Interaction Studies

In Vitro Studies

CYP450 Enzymes:

Isavuconazole is a substrate of CYP3A4 and CYP3A5. Isavuconazole is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Isavuconazole is an inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9.

Transporter Systems:

Isavuconazole is an inhibitor of P-gp-, BCRP- and OCT2.

Clinical Studies and Model-Informed Approaches

The effects of ketoconazole, rifampin, lopinavir/ritonavir, and esomeprazole on isavuconazole are shown inFigure 1.

Ketoconazole:

Lopinavir/Ritonavir:

Rifampin:

Figure 1. The Effect of Coadministered Drugs on Isavuconazole Exposure

CYP3A4 Substrates:

CRESEMBA increased the systemic exposure of sensitive CYP3A4 substrates midazolam, sirolimus and tacrolimus approximately 2-fold, and therefore CRESEMBA is a moderate inhibitor of CYP3A4.

Figure 2. The Effect of Isavuconazole on Coadministered CYP3A4 Substrate Medications

The effects of isavuconazole on other CYP substrates: caffeine, bupropion, methadone, repaglinide, warfarin, omeprazole, and dextromethorphan, are shown inFigure 3.

Figure 3. The Effect of Isavuconazole on Exposure of Coadministered CYP Substrate Medications

The effects of isavuconazole on the substrates of UGT and transporters: mycophenolate mofetil (MMF), methotrexate, metformin, and digoxin are shown inFigure 4.

Figure 4. The Effect of Isavuconazole on Exposure on the Substrates of UGT and Transporters

Vincristine:

Vincristine (P-gp substrate) exposure is predicted to increase by less than 2-fold in pediatric and adult patients following concomitant administration with CRESEMBA.

(

12.3 Pharmacokinetics

General Pharmacokinetics

Table 6. Steady State Pharmacokinetic Parameters of Isavuconazole Following Administration of 186 mg CRESEMBA Capsules
Parameter	CRESEMBA 186 mg 2 Capsules Each capsule contains the equivalent of 100 mg of isavuconazole. (n = 37)	CRESEMBA 186 mg 6 Capsules (n = 32)
C_max(mg/L)
Mean SD CV %	7.5 1.9 25.2	20.0 3.6 17.9
t_max(hr)
Median Range	3.0 2.0 – 4.0	4.0 2.0 – 4.0
AUC (mg•hr/L)
Mean SD CV %	121.4 35.8 29.5	352.8 72.0 20.4

Absorption

CRESEMBA given orally as an intravenous solution administered via nasogastric (NG) tube provides systemic isavuconazole exposure that is similar to the oral capsule (Table 7).

Table 7. Statistical Comparison of Plasma Pharmacokinetics of Isavuconazole Following Single Oral Dose Administration of 2 Capsules of 186 mg (Equivalent to 200 mg Isavuconazole) and Single Intravenous Solution Dose Administration of 372 mg (Equivalent to 200 mg Isavuconazole) via Nasogastric (NG) Tube in Healthy Adult Subjects Under Fasted Conditions
	CRESEMBA IV Solution via NG Tube		CRESEMBA Oral Capsules		NG Tube/Oral Capsule
Pharmacokinetic Parameter	N	Mean (%CV)	N	Mean (%CV)	GMR (90% CI)
C_max(mg/L)	13	2.3 (23.6)	13	2.2 (26.7)	105.34 (89-124)
AUC_0-72hr (mg·hr/L)	13	34.9 (22.1)	13	35.8 (24.6)	97.81 (93-103)
AUC_0-∞ (mg·hr/L)	12	98.1 (44.5)	12	100.1 (46.8)	99.27 (93-106)
GMR = Geometric least-squares mean ratio; CI = confidence interval

Effect of Food

Coadministration of CRESEMBA equivalent to isavuconazole 400 mg oral dose with a high-fat meal reduced isavuconazole C_maxby 9% and increased AUC by 9%. CRESEMBA can be taken with or without food.

Distribution

Elimination

Metabolism

in vitro

In vivo

studies indicate that CYP3A4, CYP3A5 and subsequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole.

Excretion

Renal excretion of isavuconazole itself was less than 1% of the dose administered.

Special populations

Geriatric Patients

Pediatric Patients

Table 8. Derived Steady State Isavuconazole AUC (mg•hr/L) values in Pediatric Patients, by Age Group
Dosage	15 mg/kg Estimated AUCss values of 15 mg/kg that were derived from existing values of pediatric patients that received 10 mg/kg of CRESEMBA for injection administered intravenously.	10 mg/kg CRESEMBA for injection administered intravenously.	10 mg/kg or Maximum Dose of 372 mg CRESEMBA for injection administered intravenously or CRESEMBA capsules administered orally.
Age Group	1 to < 3 years (n=5)	3 to < 6 years (n=10)	6 to < 12 years (n=29)	12 to < 18 years (n=29)
Mean	80.2	103.3	97.3	104.2
Median	64.3	110.3	87.7	97.7
Minimum - Maximum	53.7 - 155	51.5 – 159.1	37.8– 153.8	35.5 – 215.6

Race

Gender

AUC estimates were similar between young female and male subjects (18 years to 45 years). There was a difference in AUC for elderly females

(see

Geriatric

section above)

. No dose adjustment is required based on gender.

Patients with Renal Impairment

Isavuconazole is not readily dialyzable. A dose adjustment is not warranted in patients with ESRD.

Patients with Hepatic Impairment

Drug Interaction Studies

In Vitro Studies

CYP450 Enzymes:

Isavuconazole is a substrate of CYP3A4 and CYP3A5. Isavuconazole is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Isavuconazole is an inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9.

Transporter Systems:

Isavuconazole is an inhibitor of P-gp-, BCRP- and OCT2.

Clinical Studies and Model-Informed Approaches

The effects of ketoconazole, rifampin, lopinavir/ritonavir, and esomeprazole on isavuconazole are shown inFigure 1.

Ketoconazole:

Lopinavir/Ritonavir:

Rifampin:

Figure 1. The Effect of Coadministered Drugs on Isavuconazole Exposure

CYP3A4 Substrates:

CRESEMBA increased the systemic exposure of sensitive CYP3A4 substrates midazolam, sirolimus and tacrolimus approximately 2-fold, and therefore CRESEMBA is a moderate inhibitor of CYP3A4.

Figure 2. The Effect of Isavuconazole on Coadministered CYP3A4 Substrate Medications

The effects of isavuconazole on other CYP substrates: caffeine, bupropion, methadone, repaglinide, warfarin, omeprazole, and dextromethorphan, are shown inFigure 3.

Figure 3. The Effect of Isavuconazole on Exposure of Coadministered CYP Substrate Medications

The effects of isavuconazole on the substrates of UGT and transporters: mycophenolate mofetil (MMF), methotrexate, metformin, and digoxin are shown inFigure 4.

Figure 4. The Effect of Isavuconazole on Exposure on the Substrates of UGT and Transporters

Vincristine:

Vincristine (P-gp substrate) exposure is predicted to increase by less than 2-fold in pediatric and adult patients following concomitant administration with CRESEMBA.

)],

which may increase the risk of vincristine-related adverse reactions.

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