Isavuconazonium Sulfate

Administration

Administer orally or by IV infusion.1

Oral Administration

Administer capsules orally without regard to meals.1

Swallow whole; do not chew, crush, dissolve, or open.1

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer only by IV infusion;1 do not administer by rapid or direct IV injection.1

Must be reconstituted and further diluted prior to IV infusion.1

Do not infuse simultaneously with other IV drugs.1

If same IV line used for sequential infusion of several different drugs, flush IV line with 0.9% sodium chloride or 5% dextrose injection before and after infusion.1

Must be infused using infusion set with inline membrane filter with pore size of 0.2–1.2 mcm.1

Vials contain no preservatives;1 for single use only.1

Reconstitute vial containing 372 mg of isavuconazonium sulfate by adding 5 mL of sterile water for injection.1 Gently shake to dissolve the lyophilized powder.1

Inspect for particulate matter and discoloration;1 reconstituted solution should appear clear and free of visible particulates.1

Immediately dilute reconstituted solution or, alternatively, store at <25°C for maximum of 1 hour prior to dilution.1

To dilute, remove 5 mL of reconstituted solution from vial and add to IV bag containing 250 mL of 0.9% sodium chloride injection or 5% dextrose injection to provide a solution containing approximately 1.5 mg of isavuconazonium sulfate per mL.1

Translucent to white particulates of isavuconazole may be visible in the diluted solution;1 gently mix or roll IV bag to minimize formation of particulates.1 Avoid unnecessary vibration or vigorous shaking;1 do not transport the solution using a pneumatic transport system.1

Because the reconstituted and diluted solution must be administered using infusion set with inline membrane filter with a pore size of 0.2–1.2 mcm, apply reminder sticker to the IV bag.1

Complete IV infusion within 6 hours after dilution when stored at room temperature.1 If refrigerated at 2–8°C immediately after dilution, complete IV infusion within 24 hours after dilution.1

Administer by IV infusion over ≥1 hour.1

Dosage

Available as isavuconazonium sulfate (inactive prodrug of isavuconazole);1 dosage expressed in terms of isavuconazonium sulfate.1

Each 186 mg of isavuconazonium sulfate is equivalent to 100 mg of isavuconazole.1

Oral and IV dosages are identical.1 Switching between oral and IV routes is acceptable;1 loading dosage not needed when switching between oral and IV preparations.1

Adults

Loading dosage of 372 mg every 8 hours for 6 doses;1 12–24 hours after final loading dose, begin maintenance dosage of 372 mg once every 24 hours.1

Base total duration of treatment on severity of underlying disease, recovery from immunosuppression, and response to the drug.1 In a clinical study, mean duration of treatment was 47 days and protocol-defined maximum treatment duration was 84 days.1 IDSA recommends treatment of invasive pulmonary aspergillosis be continued for at least 6–12 weeks and continued throughout period of immunosuppression.423

Loading dosage of 372 mg every 8 hours for 6 doses;1 12–24 hours after final loading dose, begin maintenance dosage of 372 mg once every 24 hours.1

Base total duration of treatment on severity of underlying disease, recovery from immunosuppression, and response to the drug.1 In a clinical study, median duration of treatment was 102, 33, or 85 days in those receiving the drug for initial treatment (primary treatment), disease refractory to other antifungal therapy, or intolerance to other antifungal therapy, respectively.1 3

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment (Child-Pugh class A or B): Manufacturer states dosage adjustments not necessary.1 Some clinicians suggest that reduced dosage be considered.12

Severe hepatic impairment (Child-Pugh class C): Dosage recommendations not available;1 pharmacokinetics not studied.1 Use in such patients only when benefits outweigh risks.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Dosage adjustments not needed in adults with mild, moderate, or severe renal impairment, including those with end-stage renal disease.1 (See Renal Impairment under Cautions.)

Geriatric Patients

Dosage adjustments not needed based on age and gender.1

Absorption

Bioavailability

Following oral or IV administration, isavuconazonium sulfate is rapidly and almost completely (>98%) hydrolyzed by esterases in the blood to yield the active moiety, isavuconazole, and an inactive cleavage product.1 10 11

Well absorbed following oral administration (absolute bioavailability 98%).1

Peak plasma concentrations achieved in approximately 2–4 hours after oral administration1 10 11 or 0.7–1 hour after start of IV infusion.1 10

Food

Administration with high-fat meal has no clinically important effect on oral absorption.1

Plasma Concentrations

Steady-state concentrations probably not achieved until after 2 weeks.11

Special Populations

Reduced bioavailability possible in patients with Roux-en-Y gastric bypass.13

Distribution

Extent

Extensively distributed into tissues.1 10

Distributed into milk in rats.1

Plasma Protein Binding

>99% (mainly albumin).1 10

Elimination

Metabolism

In vivo studies indicate isavuconazole is metabolized by CYP3A4 and 3A5 and, subsequently, by UGT.1

Elimination Route

Following oral administration of radiolabeled isavuconazonium sulfate, 46% of total radioactive dose recovered in feces (approximately 33% as isavuconazole) and 46% recovered in urine (principally as metabolites of isavuconazole and metabolites of the inactive cleavage product).1 4

Only negligible amounts (<1%) of a dose of isavuconazonium sulfate are eliminated in urine as active isavuconazole.1 10

Isavuconazole is not readily dialyzable.1

Half-life

Single-dose study in adults using oral or IV isavuconazonium sulfate indicates mean distribution half-life of isavuconazole is 1.7–2.1 or 0.42–1.6 hours, respectively, and mean terminal elimination half-life of isavuconazole is 56–77 or 76–104 hours, respectively.10

Special Populations

Mild or moderate hepatic impairment (Child-Pugh class A or B): Mean AUC increased by 64 or 84%. respectively.1 After IV administration, half-life increased to 224 or 302 hours, respectively, compared with 123 hours in healthy individuals.12

Mild, moderate, or severe renal impairment: Pharmacokinetics not altered.1

Geriatric patients: Pharmacokinetics not affected by age.1

• Triazole antifungal;1 5 6 7 9 structurally similar to fluconazole and voriconazole.7 22

• Isavuconazonium is a prodrug and is inactive until hydrolyzed in the blood to isavuconazole.1 6 7 9

• Like other triazole antifungals, inhibits 14-α-demethylase, which leads to accumulation of methylated sterols (e.g., 14-α-methylated lanosterol, 4,14-dimethylzymosterol, 24-methylenedihydrolanosterol) and decreased concentrations of ergosterol in fungal cell membranes.1 6 7 Depletion of ergosterol affects cell membrane integrity and function and can lead to fungal cell death.1 6 7

• Aspergillus: Active in vitro and in clinical infections against A. flavus,1 14 19 20 21 A. fumigatus,1 14 19 20 21 and A. niger.1 14 19 20 21 Also has in vitro activity against A. nidulans14 20 21 and A. terreus.14 19 20 21

• Mucorales: Active in vitro and in clinical infections against fungi in the order Mucorales, including Rhizopus (R. oryzae, R. azygospurus, R. microspores),1 19 Mucor (M. amphibiorum,1 M. circinelloides1 14 ), Lichtheimia (L. corymbifera; formerly Absidia corymbifera),1 14 and Rhizomucor (R. pusillus).1 14 19

• Candida: Active in vitro against C. albicans,14 19 20 C. dublinensis,14 19 C. glabrata,14 18 19 20 C. guilliermondii,14 18 19 C. krusei,14 18 19 20 C. lusitaniae,14 19 C. parapsilosis,14 19 20 and C. tropicalis.14 19 20 Has in vitro activity against some Candida that have resistance or reduced susceptibility to fluconazole.6 14 19

• Other fungi: Active in vitro against Blastomyces dermatitidis,14 Coccidioides posadasii,14 Cryptococcus gattii,14 C. neoformans,14 19 Geotrichum capitatum,14 Histoplasma capsulatum,14 Penicillium,19 Pichia,14 Rhodotorula,14 Saccharomyces cerevisiae,14 Scedosporium,14 19 Trichosporon,14 19 and dermatophytes (Trichophyton rubrum, T. mentagrophytes, T. tonsurans, Epidermophyton floccosum, Microsporum canis).14

• Resistance or reduced susceptibility to isavuconazole may occur.1 5 6 14 18 22 Cross-resistance can occur between isavuconazole and other azole antifungals (e.g., itraconazole, voriconazole).1 5 19 22

Note: Dosage expressed as milligrams of isavuconazonium sulfate; switching between the intravenous (IV) and oral formulations of isavuconazonium sulfate is acceptable; for maintenance dosing, it is not necessary to restart dosing with the initial dose regimen when switching between formulations.

Aspergillosis, invasive:

IV: Initial: 372 mg (isavuconazole 200 mg) every 8 hours for 6 doses; Maintenance: 372 mg (isavuconazole 200 mg) once daily. Start maintenance dose 12 to 24 hours after the last loading dose.

Oral: Initial: 372 mg (isavuconazole 200 mg) every 8 hours for 6 doses; Maintenance: 372 mg (isavuconazole 200 mg) once daily. Start maintenance dose 12 to 24 hours after the last loading dose.

Duration of therapy: Minimum of 6 to 12 weeks, although duration is highly dependent on degree/duration of immunosuppression, disease site, and evidence of disease improvement (IDSA [Patterson 2016])

Mucormycosis, invasive:

IV: Initial: 372 mg (isavuconazole 200 mg) every 8 hours for 6 doses; Maintenance: 372 mg (isavuconazole 200 mg) once daily. Start maintenance dose 12 to 24 hours after the last loading dose.

Oral: Initial: 372 mg (isavuconazole 200 mg) every 8 hours for 6 doses; Maintenance: 372 mg (isavuconazole 200 mg) once daily. Start maintenance dose 12 to 24 hours after the last loading dose.

Refer to adult dosing.

Mild or moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary.

Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use with caution.

Adverse events were observed in animal reproduction studies. Based on animal data, isavuconazonium sulfate may have the potential to increase the risk of adverse developmental events if used in pregnant women.