Isavuconazonium (Monograph)

Brand name: Cresemba
Drug class: Azoles
Chemical name: [2-[[[1-[1-[(2R,3R)-3-[4-( 4-Cyanophenyl)-2-thiazolyl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-4H-1,2,4-triazolium-4-yl]ethoxy]carbonyl]methylamino]-3-pyridinyl]methyl ester-N-methyl-glycine sulfate (1:1)
Molecular formula: C₃₅H₃₅F₂N₈O₅S•HO₄SC₂₂H₁₇F₂N₅OS
CAS number: 946075-13-4

Medically reviewed by Drugs.com on Aug 30, 2023. Written by ASHP.

Introduction

Antifungal; azole (triazole derivative); prodrug of isavuconazole.^{1 5 6 7 8}

Uses for Isavuconazonium

Aspergillosis

Treatment of invasive aspergillosis;^{1 8 29} designated an orphan drug by FDA for this indication.²

IDSA considers IV voriconazole the drug of choice for primary treatment of invasive aspergillosis;⁴²³ amphotericin B and isavuconazonium recommended as alternatives for primary treatment.⁴²³ For salvage therapy in patients refractory to or intolerant of primary antifungal therapy, IDSA recommends IV amphotericin B, an IV echinocandin (caspofungin, micafungin), oral or IV posaconazole, or itraconazole oral suspension.⁴²³

Consult current IDSA clinical practice guidelines available at [Web] for additional information on management of aspergillosis.⁴²³

Mucormycosis

Treatment of invasive mucormycosis;^{1 8 30} designated an orphan drug by FDA for this indication.²

Esophageal Candidiasis

Treatment of esophageal candidiasis^{† [off-label]}.^{16 440}

Esophageal candidiasis requires treatment with a systemic antifungal (not a topical antifungal).^{425 440}

IDSA recommends oral fluconazole as the preferred drug of choice for treatment of esophageal candidiasis;⁴²⁵ if oral therapy not tolerated, IV fluconazole or an IV echinocandin (anidulafungin, caspofungin, micafungin) recommended.⁴²⁵

For treatment of esophageal candidiasis in HIV-infected adults, CDC, NIH, and IDSA recommend oral or IV fluconazole or itraconazole oral solution.⁴⁴⁰ Oral or IV voriconazole, oral isavuconazonium, an IV echinocandin (anidulafungin, caspofungin, micafungin), or IV amphotericin B recommended as alternatives.⁴⁴⁰

Consult current IDSA clinical practice guidelines available at [Web]⁴²⁵ and current CDC, NIH, and IDSA clinical practice guidelines for prevention and treatment of opportunistic infections in HIV-infected individuals available at [Web]⁴⁴⁰ for additional information on management of esophageal candidiasis.

Candidemia and Other Invasive Candida Infections

Has been used for treatment of candidemia and other invasive infections caused by Candida^{† [off-label]};¹⁷ designated an orphan drug by FDA for treatment of invasive candidiasis/candidemia.²

Isavuconazonium Dosage and Administration

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 µm.¹

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

Reconstitution and Dilution

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 µm, 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

Rate of Administration

Administer by IV infusion over ≥1 hour.¹

Dosage

Available as isavuconazonium sulfate (inactive prodrug of isavuconazole).¹

Dosage usually expressed in terms of isavuconazonium sulfate;¹ also has been expressed in terms of isavuconazole.^{8 16 17 423 440}

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

Aspergillosis

Oral or IV

Loading dosage of 372 mg of isavuconazonium sulfate (equivalent to 200 mg of isavuconazole) every 8 hours for 6 doses;^{1 423} 12–24 hours after final loading dose, begin maintenance dosage of 372 mg of isavuconazonium sulfate (equivalent to 200 mg of isavuconazole) once every 24 hours.^{1 423}

Base total duration of treatment on severity of underlying disease, recovery from immunosuppression, and response to the drug.^{1 423} In a clinical study, mean duration of treatment was 45 days and protocol-defined maximum treatment duration was 84 days.²⁹ IDSA recommends treatment of invasive pulmonary aspergillosis be continued for at least 6–12 weeks.⁴²³

Mucormycosis

Oral or IV

Loading dosage of 372 mg of isavuconazonium sulfate (equivalent to 200 mg of isavuconazole) every 8 hours for 6 doses;¹ 12–24 hours after final loading dose, begin maintenance dosage of 372 mg of isavuconazonium sulfate (equivalent to 200 mg of isavuconazole) 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}

Esophageal Candidiasis† [off-label]

Oral

HIV-infected adults: Loading dose of 372 mg of isavuconazonium sulfate (equivalent to 200 mg of isavuconazole) followed by 93 mg of isavuconazonium sulfate (equivalent to 50 mg of isavuconazole) once daily or loading dose of 744 mg of isavuconazonium sulfate (equivalent to 400 mg of isavuconazole) followed by 186 mg of isavuconazonium sulfate (equivalent to 100 mg of isavuconazole) once daily.⁴⁴⁰ Alternatively, 744 mg of isavuconazonium sulfate (equivalent to 400 mg of isavuconazole) once weekly.⁴⁴⁰

CDC, NIH, and IDSA recommend treatment of esophageal candidiasis be continued for 14–21 days.⁴⁴⁰

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

Cautions for Isavuconazonium

Contraindications

• Hypersensitivity to isavuconazole (active metabolite of isavuconazonium).¹

• Familial short QT syndrome.¹ (See Cardiovascular Effects under Cautions.)

• Concomitant use with potent CYP3A4 inhibitors or inducers.¹ (See Interactions.)

Warnings/Precautions

Sensitivity Reactions

Serious hypersensitivity (e.g., anaphylaxis) and severe skin reactions (e.g., Stevens-Johnson syndrome) reported in patients receiving other azole antifungals.¹

Data regarding cross-sensitivity with other azole antifungals not available.¹ Use with caution in patients hypersensitive to other azoles.¹

If severe adverse cutaneous reaction occurs, discontinue isavuconazonium.¹

Hepatic Effects

Serious hepatic effects, including hepatitis, cholestasis, and hepatic failure (sometimes fatal), reported in patients with serious underlying medical conditions (e.g., hematologic malignancy) receiving an azole antifungal, including isavuconazonium.¹

Less severe hepatic effects (e.g., increased ALT, AST, alkaline phosphatase, total bilirubin concentrations) also reported.¹ Liver function test elevations generally were reversible and did not require discontinuance of isavuconazonium.¹

Perform liver function tests prior to and monitor during isavuconazonium therapy.¹ If abnormal liver function tests occur during therapy, monitor for development of more severe hepatic injury.¹ If signs and symptoms of liver disease occur, discontinue isavuconazonium.¹

Infusion Reactions

Infusion reactions (e.g., hypotension, dyspnea, chills, dizziness, paresthesia, hypoesthesia) reported.¹

To reduce risk of infusion reactions, dilute reconstituted solution in 250 mL of compatible diluent and administer by IV infusion over ≥1 hour.¹ (See IV Administration under Dosage and Administration.)

If infusion reaction occurs, discontinue the IV infusion.¹

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.¹ Has been associated with increased perinatal mortality and skeletal abnormalities in animals;¹ skeletal abnormalities also observed in animal studies evaluating other azole antifungals.¹

Use during pregnancy only if potential benefits to the woman outweigh potential risks to fetus.¹ (See Pregnancy under Cautions.)

Cardiovascular Effects

Shortens corrected QT (QT_c) interval in a dose-related manner.¹ Contraindicated in patients with familial short QT syndrome (see Contraindications under Cautions).¹ Concomitant use with other drugs that shorten QT_c interval not evaluated.¹ (See Drugs that Shorten the QT Interval under Interactions.)

Atrial fibrillation, atrial flutter, bradycardia, palpitations, supraventricular extrasystoles, supraventricular tachycardia, ventricular extrasystoles, and cardiac arrest also reported.¹

Interactions

Concomitant use with drugs that are potent CYP3A4 inhibitors (e.g., ketoconazole, high-dose ritonavir) or inducers (e.g., rifampin, carbamazepine, St. John's wort [Hypericum perforatum], long-acting barbiturates) is contraindicated.¹ (See Interactions.)

Administration Precautions

IV solutions of isavuconazonium must be given by IV infusion through an inline filter to remove any insoluble particulates that may be present.¹ (See IV Administration under Dosage and Administration.)

Selection and Use of Antifungals

Prior to initiation of isavuconazonium, obtain appropriate specimens for fungal culture and other relevant laboratory studies (including histopathology) to isolate and identify causative organism(s).¹ May be started pending availability of results, but adjust antifungal therapy as needed when results become available.¹

Information on test methods and quality control standards for in vitro susceptibility testing of antifungal agents and specific interpretive criteria for such testing recognized by FDA is available at [Web].¹

Specific Populations

Pregnancy

Category C.¹

Use during pregnancy only if potential benefits to the woman justify potential risks to fetus.¹

No adequate and well-controlled studies in pregnant women.¹ Based on data from animal reproduction studies, isavuconazonium is predicted to have the potential for increasing the risk of adverse developmental outcomes above background risk.¹

Lactation

Distributed into milk in rats.¹ Do not breast-feed while receiving isavuconazonium.¹

Pediatric Use

Safety and efficacy not established in patients <18 years of age.¹

Geriatric Use

No substantial difference in pharmacokinetics between geriatric and younger adults.¹

Hepatic Impairment

Mild or moderate hepatic impairment (Child-Pugh class A or B): AUC increased, systemic clearance decreased, half-life prolonged.^{1 12} Clinical importance unknown.¹²

Severe hepatic impairment (Child-Pugh class C): Use isavuconazonium only if benefits outweigh risks.¹ If used in such patients, monitor for adverse effects.¹ Pharmacokinetics not evaluated.¹

Renal Impairment

Mild, moderate, or severe renal impairment: No clinically important effects on pharmacokinetics.¹

Common Adverse Effects

GI effects (nausea, vomiting, diarrhea, abdominal pain, constipation, dyspepsia, decreased appetite),¹ elevated bilirubin and liver enzymes (e.g., ALT, AST, alkaline phosphatase, γ-glutamyltransferase),¹ metabolic effects (hypokalemia, hypomagnesemia),¹ respiratory effects (dyspnea, cough, acute respiratory failure),¹ headache,¹ fatigue,¹ insomnia,¹ back pain,¹ chest pain,¹ peripheral edema,¹ hypotension,¹ renal failure,¹ delirium (e.g., agitation, confusional state, disorientation, mental status changes),¹ anxiety,¹ rash,¹ pruritus,¹ administration site reactions.¹

Drug Interactions

Because isavuconazonium rapidly metabolized to isavuconazole in vivo, interactions are reported for isavuconazole.¹

Isavuconazole is metabolized by CYP3A4 and 3A5 and subsequently by UGT.¹

Moderate inhibitor of CYP3A4;¹ inhibits CYP2C8, 2C9, 2C19, and 2D6 in vitro.¹ Induces CYP3A4, 2B6, 2C8, and 2C9 in vitro.¹

Weak inhibitor of P-glycoprotein (P-gp) and organic cation transporter (OCT) 2.¹ Also inhibits breast cancer resistance protein (BCRP).¹ Does not inhibit organic anion transporting polypeptide (OATP) 1B1 or OATP1B3.¹⁵

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Concomitant use with potent CYP3A4 inhibitors or inducers may increase or decrease plasma concentrations of isavuconazole, respectively, and is contraindicated.¹

Drugs Affecting or Affected by Membrane Transporters

If used concomitantly with drugs that are P-gp substrates and have a narrow therapeutic index, dosage adjustment of the P-gp substrate may be required.¹

Drugs that Shorten the QT Interval

Possibility of additive effects if used concomitantly with drugs that shorten the QT interval not evaluated to date.¹ (See Cardiovascular Effects under Cautions.)

Specific Drugs

Isavuconazonium Pharmacokinetics

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 administration^{1 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

Stability

Storage

Oral

Capsules

20–25°C (may be exposed to 15–30°C);¹ store in original package and protect from moisture.¹

Parenteral

Powder for IV Infusion

2–8°C.¹

Dilute immediately after reconstitution;¹ alternatively, may be stored at <25°C for a maximum of 1 hour prior to dilution.¹

Total time from dilution to completion of IV infusion should not exceed 6 hours when stored at room temperature or 24 hours when refrigerated at 2–8°C immediately after dilution.¹ Do not freeze.¹

Compatibility

Parenteral

Solution Compatibility1 HID

Drug CompatibilityHID

Actions and Spectrum

• Triazole antifungal;^{1 5 6 7 8 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 8 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 8} 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 8 14 19 20 21 23 24} A. fumigatus,^{1 8 14 19 20 21 23 24} and A. niger.^{1 8 14 19 20 21 23 24} Also has in vitro activity against A. lentulus,^{8 23} A. nidulans,^{8 14 20 21 23 24} A. sydowii,²³ A. terreus,^{8 14 19 20 21 23 24} A. versicolor,⁸ and A. welsitschiae.²³

• Mucorales: Active in vitro and in clinical infections against fungi in the order Mucorales, including Rhizopus (R. oryzae, R. azygospurus, R. microsporus),^{1 8 19} Mucor (M. amphibiorum,¹ M. circinelloides^{1 8 14} ), Lichtheimia (L. corymbifera; formerly Absidia corymbifera),^{1 8 14} and Rhizomucor (R. pusillus).^{1 8 14 19} In vitro, less active against Mucorales compared with Aspergillus.^{8 23}

• Candida: Active in vitro against C. albicans,^{8 14 19 20 23 24 28} C. dubliniensis,^{8 14 19 23 24} C. glabrata,^{8 14 18 19 20 23 24 28} C. guilliermondii,^{8 14 18 19 23} C. kefyr,^{23 28} C. krusei,^{8 14 18 19 20 23 24 28} C. lusitaniae,^{8 14 19 23 28} C. orthopsilosis,^{8 23} C. parapsilosis,^{8 14 19 20 23 24 28} and C. tropicalis.^{8 14 19 20 23 24 28} Some strains of C. auris (often misidentified as C. haemulonii, C. famata, or Rhodotorula glutinis) inhibited in vitro by isavuconazole concentrations of 0.004–0.25 mcg/mL.^{25 26 27} Has in vitro activity against some Candida with reduced susceptibility or resistance to fluconazole.^{6 14 19}

• Other fungi: Although clinical importance unclear, active in vitro against Blastomyces dermatitidis,¹⁴ Coccidioides posadasii,¹⁴ Cryptococcus gattii,^{8 14} C. neoformans,^{8 14 19 23 24} Geotrichum capitatum,^{8 14} Histoplasma capsulatum,^{8 14} Penicillium,¹⁹ Pichia,¹⁴ Rhodotorula,^{8 14} Saccharomyces cerevisiae,^{8 14 23 24} Scedosporium,^{8 14 19} Trichosporon,^{14 19} and dermatophytes (Trichophyton rubrum, T. mentagrophytes, T. tonsurans, Epidermophyton floccosum, Microsporum canis).^{8 14}

• Resistance or reduced susceptibility to isavuconazole may occur.^{1 5 6 8 14 18 22} Aspergillus^{23 24} and Candida^{23 24 28} with reduced susceptibility or resistance to isavuconazole reported.

• Cross-resistance can occur between isavuconazole and other azole antifungals (e.g., itraconazole, voriconazole).^{1 5 8 19 22 24}

Advice to Patients

• Isavuconazonium can be taken with or without food.¹

• Importance of swallowing capsules whole, without crushing, chewing, dissolving, or opening.¹

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and any concomitant illnesses (e.g., liver disease, familial short QT syndrome).¹

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

• Importance of advising patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Medical Disclaimer