Isavuconazonium Sulfate (Monograph)

Brand name: Cresemba
Drug class: Azoles

Medically reviewed by Drugs.com on Jul 10, 2024. Written by ASHP.

Introduction

Antifungal; azole (triazole derivative); prodrug of isavuconazole.

Uses for Isavuconazonium Sulfate

Aspergillosis

Treatment of invasive aspergillosis; designated an orphan drug by FDA for this indication.

Isavuconazonium for injection is indicated for use in adults and pediatric patients ≥1 year of age; capsules are indicated for use in adults and pediatric patients ≥6 years of age who weigh ≥16 kg.

IDSA considers IV voriconazole the drug of choice for primary treatment of invasive aspergillosis; amphotericin B and isavuconazonium recommended as alternatives. 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.

Mucormycosis

Treatment of invasive mucormycosis; designated an orphan drug by FDA for this indication.

Isavuconazonium for injection is indicated for use in adults and pediatric patients ≥1 year of age; capsules are indicated for use in adults and pediatric patients ≥6 years of age who weigh ≥16 kg.

The European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium global guideline strongly recommends liposomal amphotericin as first-line treatment of mucormycosis across all patterns of organ involvement. IV isavuconazonium or IV or oral posaconazole (delayed-release tablets) are moderately recommended as first-line treatments. In the salvage setting, both isavuconazonium and posaconazole are strongly recommended treatment options.

Esophageal Candidiasis

Has been used for treatment of esophageal candidiasis^{† [off-label]}.

Esophageal candidiasis requires treatment with a systemic antifungal (not a topical antifungal).

IDSA recommends oral fluconazole as the preferred drug of choice for treatment of esophageal candidiasis; if oral therapy not tolerated, IV fluconazole or an IV echinocandin (anidulafungin, caspofungin, micafungin) recommended. Isavuconazonium was recently approved when the IDSA guideline was published.

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

Candidemia and Other Invasive Candida Infections

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

Coccidioidomycosis

Has been used for treatment of coccidioidomycosis^{† [off-label]} in pulmonary and extrapulmonary sites of involvement (e.g., skin, skeletal system, meninges).

Isavuconazonium Sulfate Dosage and Administration

General

Pretreatment Screening

• Obtain specimens for fungal culture and other relevant laboratory studies (including histopathology) to isolate and identify causative organism(s) prior to initiating isavuconazonium therapy.

• Evaluate liver-related laboratory tests at the initiation of isavuconazonium therapy.

Patient Monitoring

• Evaluate liver-related laboratory tests during therapy and monitor patients who have abnormal test results for the development of more severe hepatic injury.

• Monitor for signs and symptoms of hypersensitivity reactions.

Administration

Administer orally or by IV infusion.

May administer injection formulation via nasogastric (NG) tube. Do not administer the capsules through an NG tube.

Oral Administration

Administer capsules orally without regard to meals.

Capsules intended for use in patients ≥6 years of age and ≥16 kg.

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

Nasogastric Administration

May administer isavuconazonium sulfate for injection via a NG tube in patients ≥6 years of age and ≥16 kg.

Must reconstitute lyophilized powder prior to NG administration. Reconstitute a vial containing 372 mg of isavuconazonium sulfate by adding 5 mL of sterile water for injection; the resultant solution contains 74.4 mg/mL of isavuconazonium sulfate.

Withdraw appropriate volume of reconstituted solution (based on adult or pediatric dosage regimen) from vial using an appropriate syringe and needle. Discard needle and cap syringe. For administration, remove the cap from the syringe and connect syringe to the NG tube to deliver dose. After dose delivery, administer three 5 mL water rinses to the NG tube.

For NG tube administration, store the reconstituted solution between 5-25ºC and administer within 1 hour of reconstitution.

IV Administration

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

Must be reconstituted and further diluted prior to IV infusion.

Do not infuse simultaneously with other IV drugs.

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.

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

Vials contain no preservatives; for single use only.

Reconstitution and Dilution

Reconstitute vial containing 372 mg of isavuconazonium sulfate by adding 5 mL of sterile water for injection; resultant solution contains 74.4 mg/mL of isavuconazonium sulfate. Gently shake to dissolve the lyophilized powder.

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

Immediately dilute reconstituted solution or, alternatively, store between 5-25°C for maximum of 1 hour prior to dilution.

To dilute, remove the appropriate volume of reconstituted solution from vial (based on the adult or pediatric dosage regimen) 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. A smaller volume infusion bag of compatible diluent may be used as long as the final concentration does not exceed approximately 1.5 mg/mL.

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

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.

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

Rate of Administration

Administer by IV infusion over ≥1 hour.

Dosage

Available as isavuconazonium sulfate (inactive prodrug of isavuconazole).

Dosage usually expressed in terms of isavuconazonium sulfate; also has been expressed in terms of isavuconazole.

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

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

Pediatric Patients

Aspergillosis

Oral or IV

Dosage of isavuconazonium sulfate in pediatric patients is based on dosage form, age, and body weight. Table 1 summarizes recommended loading and maintenance doses of isavuconazonium sulfate in pediatric patients.

Start maintenance doses 12 to 24 hours after the last loading dose.

Mucormycosis

For the treatment of invasive mucormycosis, the dosage of isavuconazonium sulfate in pediatric patients is based on dosage form, age, and body weight (see Table 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; 12–24 hours after final loading dose, begin maintenance dosage of 372 mg of isavuconazonium sulfate (equivalent to 200 mg of isavuconazole) once daily. Table 2 summarizes the recommended loading and maintenance doses for oral and IV dosage forms.

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

Mucormycosis

Oral or IV

Loading dosage of 372 mg of isavuconazonium sulfate (equivalent to 200 mg of isavuconazole) every 8 hours for 6 doses; 12–24 hours after final loading dose, begin maintenance dosage of 372 mg of isavuconazonium sulfate (equivalent to 200 mg of isavuconazole) once daily. See Table 2 for recommended loading and maintenance doses for oral and IV dosage forms.

Base total duration of treatment on severity of underlying disease, recovery from immunosuppression, and response to the drug. 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.

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. Alternatively, 744 mg of isavuconazonium sulfate (equivalent to 400 mg of isavuconazole) once weekly.

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

Special Populations

Hepatic Impairment

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

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

Renal Impairment

Dosage adjustments not needed in adults with mild, moderate, or severe renal impairment, including those with end-stage renal disease.

Geriatric Patients

Dosage adjustments not needed based on age.

Cautions for Isavuconazonium Sulfate

Contraindications

• Known hypersensitivity to isavuconazole (active metabolite of isavuconazonium).

• Familial short QT syndrome.

• Concomitant use with strong CYP3A4 inhibitors (e.g., ketoconazole, high-dose ritonavir) or inducers (e.g., rifampin, carbamazepine, St. John's wort [Hypericum perforatum], long-acting barbiturates).

Warnings/Precautions

Hepatic Adverse Drug Reactions

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.

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

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

Infusion-related Reactions

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

If infusion-related reaction occurs, discontinue the IV infusion.

Hypersensitivity Reactions

Serious hypersensitivity reactions (e.g., anaphylaxis, including with fatal outcome) have occurred. Symptoms including dyspnea, hypotension, generalized erythema with flushing, and urticaria reported; often occurred soon after therapy initiation.

Severe skin reactions (e.g., Stevens-Johnson syndrome) occurred in patients receiving other azole antifungals.

If an anaphylactic or severe adverse cutaneous reaction occurs, discontinue the drug and initiate supportive treatment if necessary.

No information available regarding cross-sensitivity of isavuconazonium sulfate and other azole antifungals; however, cross-sensitivity between other triazole agents reported. Monitor patients with hypersensitivity to other azoles for signs and symptoms of hypersensitivity reactions when administered isavuconazonium sulfate.

Embryo-fetal Toxicity

May cause fetal harm. Has been associated with increased perinatal mortality and skeletal abnormalities in animals. Advise pregnant women of potential fetal risk.

Advise females of reproductive potential to use an effective contraceptive method during treatment and for 28 days after the last dose.

Drug Interactions

Concomitant use with drugs that are strong CYP3A4 inhibitors (e.g., ketoconazole, high-dose ritonavir) or inducers (e.g., rifampin, carbamazepine, St. John's wort, long-acting barbiturates) is contraindicated.

Drug Particulates

Following dilution, the IV formulation may form a precipitate. Administer IV through an in-line filter.

Specific Populations

Pregnancy

No human data on use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. May cause fetal harm.

Lactation

Distributed into milk in rats; no data on the presence of the drug in human milk, the effects on the breastfed infant, or the effects on milk production. Do not breast-feed while receiving isavuconazonium.

Females and Males of Reproductive Potential

Advise female patients of reproductive potential to use effective contraception during treatment and for 28 days after the final dose.

Pediatric Use

For invasive aspergillosis, safety and efficacy of isavuconazonium sulfate for injection have been established in pediatric patients ≥1 year of age and for capsules in pediatric patients ≥6 years of age weighing ≥16 kg.

For invasive mucormycosis, safety and efficacy of isavuconazonium sulfate for injection have been established in pediatric patients ≥1 year of age and for capsules in pediatric patients ≥6 years of age weighing ≥16 kg.

Geriatric Use

No substantial difference in pharmacokinetics between geriatric and younger adults. No overall differences in efficacy or safety between geriatric and younger patients; however, greater sensitivity of some older individuals cannot be ruled out.

Hepatic Impairment

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

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

Renal Impairment

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

Common Adverse Effects

Most common adverse reactions in adults: nausea, vomiting, diarrhea, headache, elevated liver chemistry tests, hypokalemia, constipation, dyspnea, cough, peripheral edema, back pain.

Most common adverse reactions in pediatric patients: diarrhea, abdominal pain, vomiting, elevated liver chemistry tests, rash, nausea, pruritus, headache.

Drug Interactions

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

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

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

Weak inhibitor of P-glycoprotein (P-gp) and organic cation transporter (OCT) 2. Also inhibits breast cancer resistance protein (BCRP). Does not inhibit organic anion transporting polypeptide (OATP) 1B1 or OATP1B3.

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.

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.

Drugs that Shorten the QT Interval

Possibility of additive effects if used concomitantly with drugs that shorten the QT interval not evaluated to date.

Specific Drugs

Isavuconazonium Sulfate 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.

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

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

When given orally as an IV solution administered via a nasogastric tube provides systemic isavuconazole exposure that is similar to the oral capsule.

Food

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

Plasma Concentrations

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

Distribution

Extent

Extensively distributed into tissues.

Distributed into milk in rats.

Plasma Protein Binding

>99% (mainly albumin).

Elimination

Metabolism

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

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).

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

Isavuconazole is not readily dialyzable.

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.

Special Populations

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

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

Geriatric patients: Pharmacokinetics not affected by age.

Stability

Storage

Oral

Capsules

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

Parenteral

Lyophilized Powder

2–8°C.

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

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. Do not freeze.

If injection preparation is used for NG tube administration, may store reconstituted solution at 5–25°C, and use within 1 hour of reconstitution.

Actions and Spectrum

• Triazole antifungal; structurally similar to fluconazole and voriconazole.

• Isavuconazonium is a prodrug and is inactive until hydrolyzed in the blood to isavuconazole.

• 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. Depletion of ergosterol affects cell membrane integrity and function and can lead to fungal cell death.

• Aspergillus: Active in vitro and in clinical infections against A. flavus, A. fumigatus, and A. niger. Also has in vitro activity against A. lentulus, A. nidulans, A. sydowii, A. terreus, A. versicolor, and A. welsitschiae.

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

• Candida: Active in vitro against C. albicans, C. dubliniensis, C. glabrata, C. guilliermondii, C. kefyr, C. krusei, C. lusitaniae, C. orthopsilosis, C. parapsilosis, and C. tropicalis. 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. Has in vitro activity against some Candida with reduced susceptibility or resistance to fluconazole.

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

• Resistance or reduced susceptibility to isavuconazole may occur. Aspergillus and Candida with reduced susceptibility or resistance to isavuconazole reported.

• Cross-resistance can occur between isavuconazole and other azole antifungals (e.g., itraconazole, voriconazole).

Advice to Patients

• Advise patients that isavuconazonium sulfate can be taken with or without food.

• Inform patients to swallow capsules whole, without crushing, chewing, dissolving, or opening.

• Inform patients that infusion-related reactions, including hypotension, dyspnea, chills, dizziness, paresthesia, and hypoesthesia, have occurred with IV administration.

• Advise patients to inform their physician immediately if they have ever had an allergic reaction to isavuconazole or other antifungal medicines (e.g., ketoconazole, fluconazole, itraconazole, posaconazole, or voriconazole). Advise patients to discontinue therapy and seek immediate medical attention if any signs or symptoms of severe allergic reaction occur.

• Advise patients to inform their clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Advise women to inform their clinicians if they are or plan to become pregnant or plan to breastfeed. Advise female patients of reproductive potential to use effective contraception during treatment and for 28 days after the final dose.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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.

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