Isavuconazonium Sulfate (Monograph)
Brand name: Cresemba
Drug class: Azoles
Introduction
Antifungal; azole (triazole derivative); prodrug of isavuconazole.1 5 6 7 8
Uses for Isavuconazonium Sulfate
Aspergillosis
Treatment of invasive aspergillosis;1 8 29 designated an orphan drug by FDA for this indication.2
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.1
IDSA considers IV voriconazole the drug of choice for primary treatment of invasive aspergillosis;423 amphotericin B and isavuconazonium recommended as alternatives.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
Mucormycosis
Treatment of invasive mucormycosis;1 8 30 designated an orphan drug by FDA for this indication.2
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.1
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.424 IV isavuconazonium or IV or oral posaconazole (delayed-release tablets) are moderately recommended as first-line treatments.424 In the salvage setting, both isavuconazonium and posaconazole are strongly recommended treatment options.424
Esophageal Candidiasis
Has been used for 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 Isavuconazonium was recently approved when the IDSA guideline was published.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
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
Coccidioidomycosis
Has been used for treatment of coccidioidomycosis† [off-label] in pulmonary and extrapulmonary sites of involvement (e.g., skin, skeletal system, meninges).33 34 35 36 37 38 440
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.1
-
Evaluate liver-related laboratory tests at the initiation of isavuconazonium therapy.1
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.1
-
Monitor for signs and symptoms of hypersensitivity reactions.1
Administration
Administer orally or by IV infusion.1
May administer injection formulation via nasogastric (NG) tube.1 31 Do not administer the capsules through an NG tube.1
Oral Administration
Administer capsules orally without regard to meals.1
Capsules intended for use in patients ≥6 years of age and ≥16 kg.1
Swallow whole; do not chew, crush, dissolve, or open.1
Nasogastric Administration
May administer isavuconazonium sulfate for injection via a NG tube in patients ≥6 years of age and ≥16 kg.1
Must reconstitute lyophilized powder prior to NG administration.1 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.1
Withdraw appropriate volume of reconstituted solution (based on adult or pediatric dosage regimen) from vial using an appropriate syringe and needle.1 Discard needle and cap syringe.1 For administration, remove the cap from the syringe and connect syringe to the NG tube to deliver dose.1 After dose delivery, administer three 5 mL water rinses to the NG tube.1
For NG tube administration, store the reconstituted solution between 5-25ºC and administer within 1 hour of reconstitution.1
IV Administration
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; resultant solution contains 74.4 mg/mL of isavuconazonium sulfate.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 between 5-25°C for maximum of 1 hour prior to dilution.1
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.1 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.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
Pediatric Patients
Aspergillosis
Oral or IV
Dosage of isavuconazonium sulfate in pediatric patients is based on dosage form, age, and body weight.1 Table 1 summarizes recommended loading and maintenance doses of isavuconazonium sulfate in pediatric patients.1
Start maintenance doses 12 to 24 hours after the last loading dose.
Dosage Form |
Age |
Body Weight (kg) |
Loading Dose |
Maintenance Dose |
---|---|---|---|---|
Injection (372 mg/vial) |
1 to <3 years |
<18 |
15 mg/kg every 8 hours for 6 doses |
15 mg/kg once daily |
3 to <18 years |
<37 |
10 mg/kg every 8 hours for 6 doses |
10 mg/kg once daily |
|
≥37 |
One reconstituted vial (372 mg) every 8 hours for 6 doses |
One reconstituted vial (372 mg) once daily |
||
Capsules 74.5 mg |
6 to <18 years |
16 to <18 |
Two capsules (149 mg) every 8 hours for 6 doses |
Two capsules (149 mg) once daily |
18 to <25 |
Three capsules (223.5 mg) every 8 hours for 6 doses |
Three capsules (223.5 mg) once daily |
||
25 to <32 |
Four capsules (298 mg) every 8 hours for 6 doses |
Four capsules (298 mg) once daily |
||
≥32 |
Five capsules (372 mg) every 8 hours for 6 doses |
Five capsules (372 mg) once daily |
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).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 daily.1 423 Table 2 summarizes the recommended loading and maintenance doses for oral and IV dosage forms.1
Dosage Form |
Loading Dose |
Maintenance Dose |
---|---|---|
Injection (372 mg/vial) |
One reconstituted vial (372 mg) every 8 hours for 6 doses |
One reconstituted vial (372 mg) once daily |
Capsules (186 mg) |
Two 186 mg capsules (372 mg) every 8 hours for 6 doses |
Two 186 mg capsules (372 mg) once daily |
Capsules (74.5 mg) |
Five 74.5 mg capsules (372 mg) every 8 hours for 6 doses |
Five 74.5 mg capsules (372 mg) once daily |
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 daily.1 See Table 2 for recommended loading and maintenance doses for oral and IV dosage forms.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
Renal Impairment
Dosage adjustments not needed in adults with mild, moderate, or severe renal impairment, including those with end-stage renal disease.1
Geriatric Patients
Dosage adjustments not needed based on age.1
Cautions for Isavuconazonium Sulfate
Contraindications
-
Known hypersensitivity to isavuconazole (active metabolite of isavuconazonium).1
-
Familial short QT syndrome.1
-
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).1
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.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-related Reactions
Infusion-related reactions (e.g., hypotension, dyspnea, chills, dizziness, paresthesia, hypoesthesia) reported.1
If infusion-related reaction occurs, discontinue the IV infusion.1
Hypersensitivity Reactions
Serious hypersensitivity reactions (e.g., anaphylaxis, including with fatal outcome) have occurred.1 Symptoms including dyspnea, hypotension, generalized erythema with flushing, and urticaria reported; often occurred soon after therapy initiation.1
Severe skin reactions (e.g., Stevens-Johnson syndrome) occurred in patients receiving other azole antifungals.1
If an anaphylactic or severe adverse cutaneous reaction occurs, discontinue the drug and initiate supportive treatment if necessary.1
No information available regarding cross-sensitivity of isavuconazonium sulfate and other azole antifungals; however, cross-sensitivity between other triazole agents reported.1 Monitor patients with hypersensitivity to other azoles for signs and symptoms of hypersensitivity reactions when administered isavuconazonium sulfate.1
Embryo-fetal Toxicity
May cause fetal harm.1 Has been associated with increased perinatal mortality and skeletal abnormalities in animals.1 Advise pregnant women of potential fetal risk.1
Advise females of reproductive potential to use an effective contraceptive method during treatment and for 28 days after the last dose.1
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.1
Drug Particulates
Following dilution, the IV formulation may form a precipitate.1 Administer IV through an in-line filter.1
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.1 May cause fetal harm.1
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.1 Do not breast-feed while receiving isavuconazonium.1
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.1
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.1 32
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.1 32
Geriatric Use
No substantial difference in pharmacokinetics between geriatric and younger adults.1 No overall differences in efficacy or safety between geriatric and younger patients; however, greater sensitivity of some older individuals cannot be ruled out.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
Most common adverse reactions in adults: nausea, vomiting, diarrhea, headache, elevated liver chemistry tests, hypokalemia, constipation, dyspnea, cough, peripheral edema, back pain.1
Most common adverse reactions in pediatric patients: diarrhea, abdominal pain, vomiting, elevated liver chemistry tests, rash, nausea, pruritus, headache.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
Specific Drugs
Drug |
Interaction |
Comments |
---|---|---|
Atorvastatin |
Potential increased atorvastatin exposure1 |
Use concomitantly with caution;1 monitor for atorvastatin-related adverse effects1 |
Barbiturates, long-acting |
Potential decreased isavuconazole exposure1 |
Concomitant use contraindicated1 |
Bupropion |
Decreased bupropion exposure1 |
Use concomitantly with caution;1 increased bupropion dosage may be needed (do not exceed maximum recommended dosage)1 |
Caffeine |
No clinically important effects on caffeine pharmacokinetics1 15 |
|
Carbamazepine |
Potential decreased isavuconazole exposure1 |
Concomitant use contraindicated1 |
Cyclophosphamide |
Use concomitantly with caution4 |
|
Dextromethorphan |
No clinically important effects on dextromethorphan pharmacokinetics1 15 |
|
Digoxin |
Increased digoxin exposure1 |
Use concomitantly with caution;1 monitor digoxin concentrations and adjust digoxin dosage accordingly1 |
Efavirenz |
Use concomitantly with caution4 |
|
Estrogens/Progestins |
Oral contraceptives containing ethinyl estradiol and norethindrone: No clinically important effects on ethinyl estradiol or norethindrone pharmacokinetics1 15 |
|
Immunosuppressive agents (cyclosporine, mycophenolate mofetil, sirolimus, tacrolimus) |
Cyclosporine, sirolimus, tacrolimus: Increased concentrations and AUC of the immunosuppressive agent1 Mycophenolate mofetil: Increased mycophenolic acid exposure1 |
Cyclosporine, sirolimus, tacrolimus: Use concomitantly with caution;1 monitor concentrations of the immunosuppressive agent and adjust immunosuppressive agent dosage accordingly1 Mycophenolate mofetil: Use concomitantly with caution;1 monitor for mycophenolic acid-related toxicities1 |
Ketoconazole |
Increased peak concentrations and AUC of isavuconazole1 |
Concomitant use contraindicated1 |
Metformin |
No clinically important effects on metformin pharmacokinetics1 15 |
|
Methadone |
No clinically important effects on methadone pharmacokinetics1 15 |
|
Methotrexate |
No clinically important effects on methotrexate pharmacokinetics1 15 |
|
Midazolam |
Increased midazolam exposure1 |
Use concomitantly with caution;1 consider reducing midazolam dosage1 |
Prednisone |
No clinically important effects on prednisone pharmacokinetics1 15 |
|
Proton-pump inhibitors (esomeprazole, omeprazole) |
Esomeprazole: No clinically important effects on isavuconazole pharmacokinetics1 Omeprazole: No clinically important effects on omeprazole pharmacokinetics1 15 |
|
Repaglinide |
No clinically important effects on repaglinide pharmacokinetics1 15 |
|
Rifampin |
Decreased peak concentrations and AUC of isavuconazole1 |
Concomitant use contraindicated1 |
St. John's wort (Hypericum perforatum) |
Potential decreased isavuconazole exposure1 |
Concomitant use contraindicated1 |
Vincristine |
Potential increased exposure and adverse effects to vincristine1 |
Avoid concomitant use; may increase the risk of vincristine-related adverse reactions1 |
Warfarin |
No clinically important effects on warfarin pharmacokinetics1 15 |
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.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
When given orally as an IV solution administered via a nasogastric tube provides systemic isavuconazole exposure that is similar to the oral capsule.1 31
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
Distribution
Extent
Extensively distributed into tissues.1 10
Distributed into milk in rats.1
Plasma Protein Binding
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
Lyophilized Powder
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
If injection preparation is used for NG tube administration, may store reconstituted solution at 5–25°C, and use within 1 hour of reconstitution.1
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. circinelloides1 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 Aspergillus23 24 and Candida23 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
-
Advise patients that isavuconazonium sulfate can be taken with or without food.1
-
Inform patients to swallow capsules whole, without crushing, chewing, dissolving, or opening.1
-
Inform patients that infusion-related reactions, including hypotension, dyspnea, chills, dizziness, paresthesia, and hypoesthesia, have occurred with IV administration.1
-
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).1 Advise patients to discontinue therapy and seek immediate medical attention if any signs or symptoms of severe allergic reaction occur.1
-
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.1
-
Advise women to inform their clinicians if they are or plan to become pregnant or plan to breastfeed.1 Advise female patients of reproductive potential to use effective contraception during treatment and for 28 days after the final dose.1
-
Inform patients of other important precautionary information.1
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.
Routes |
Dosage Forms |
Strengths |
Brand Names |
Manufacturer |
---|---|---|---|---|
Oral |
Capsules |
74.5 mg (equivalent to 40 mg isavuconazole) |
Cresemba |
|
186 mg (equivalent to 100 mg isavuconazole) |
Cresemba |
Astellas |
||
Parenteral |
For injection, for IV infusion |
372 mg (equivalent to 200 mg isavuconazole) |
Cresemba |
Astellas |
AHFS DI Essentials™. © Copyright 2025, Selected Revisions July 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.
References
1. Astellas Pharma US, Inc. Cresemba (isavuconazonium sulfate) capsules and for injection prescribing information. Northbrook, IL; 2023 Dec.
2. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Rockville, MD. From FDA website. Accessed 2015 Apr 13. http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm
3. Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 207500Orig1s000/207501Orig1s000: Medical review(s). From FDA website. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207500Orig1207501Orig1s000MedR.pdf
4. Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 207500Orig1s000/207501Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207500Orig1207501Orig1s000ClinPharmR.pdf
5. Fera MT, La Camera E, De Sarro A. New triazoles and echinocandins: mode of action, in vitro activity and mechanisms of resistance. Expert Rev Anti Infect Ther. 2009; 7:981-98. https://pubmed.ncbi.nlm.nih.gov/19803707
6. Falci DR, Pasqualotto AC. Profile of isavuconazole and its potential in the treatment of severe invasive fungal infections. Infect Drug Resist. 2013; 6:163-74. https://pubmed.ncbi.nlm.nih.gov/24187505
7. Girmenia C. New generation azole antifungals in clinical investigation. Expert Opin Investig Drugs. 2009; 18:1279-95. https://pubmed.ncbi.nlm.nih.gov/19678798
8. Ananda-Rajah MR, Chang CC, and Slavin MA. Isavuconazole. In: Grayson ML, ed. Kucers' the use of antibiotics: a clinical review of antibacterial, antifungal, antiparasitic, and antiviral drugs. 7th ed. Boca Raton, FL: CRC Press; 2018:2858-69.
9. Livermore J, Hope W. Evaluation of the pharmacokinetics and clinical utility of isavuconazole for treatment of invasive fungal infections. Expert Opin Drug Metab Toxicol. 2012; 8:759-65. https://pubmed.ncbi.nlm.nih.gov/22530880
10. Schmitt-Hoffmann A, Roos B, Heep M et al. Single-ascending-dose pharmacokinetics and safety of the novel broad-spectrum antifungal triazole BAL4815 after intravenous infusions (50, 100, and 200 milligrams) and oral administrations (100, 200, and 400 milligrams) of its prodrug, BAL8557, in healthy volunteers. Antimicrob Agents Chemother. 2006; 50:279-85. https://pubmed.ncbi.nlm.nih.gov/16377698
11. Schmitt-Hoffmann A, Roos B, Maares J et al. Multiple-dose pharmacokinetics and safety of the new antifungal triazole BAL4815 after intravenous infusion and oral administration of its prodrug, BAL8557, in healthy volunteers. Antimicrob Agents Chemother. 2006; 50:286-93. https://pubmed.ncbi.nlm.nih.gov/16377699
12. Schmitt-Hoffmann A, Roos B, Spickermann J et al. Effect of mild and moderate liver disease on the pharmacokinetics of isavuconazole after intravenous and oral administration of a single dose of the prodrug BAL8557. Antimicrob Agents Chemother. 2009; 53:4885-90. https://pubmed.ncbi.nlm.nih.gov/19667286
14. Thompson GR, Wiederhold NP. Isavuconazole: a comprehensive review of spectrum of activity of a new triazole. Mycopathologia. 2010; 170:291-313. https://pubmed.ncbi.nlm.nih.gov/20524153
15. Astellas, Northbrook, IL: Personal Communication.
16. Viljoen J, Azie N, Schmitt-Hoffmann AH et al. A phase 2, randomized, double-blind, multicenter trial to evaluate the safety and efficacy of three dosing regimens of isavuconazole compared with fluconazole in patients with uncomplicated esophageal candidiasis. Antimicrob Agents Chemother. 2015; 59:1671-9. https://pubmed.ncbi.nlm.nih.gov/25561337
17. Kullberg BJ, Viscoli C, Pappas PG et al. Isavuconazole versus Caspofungin in the Treatment of Candidemia and Other Invasive Candida Infections: The ACTIVE Trial. Clin Infect Dis. 2018; https://pubmed.ncbi.nlm.nih.gov/30289478
18. Castanheira M, Messer SA, Rhomberg PR et al. Isavuconazole and nine comparator antifungal susceptibility profiles for common and uncommon Candida species collected in 2012: application of new CLSI clinical breakpoints and epidemiological cutoff values. Mycopathologia. 2014; 178:1-9. https://pubmed.ncbi.nlm.nih.gov/24952015
19. Pfaller MA, Messer SA, Rhomberg PR et al. In vitro activities of isavuconazole and comparator antifungal agents tested against a global collection of opportunistic yeasts and molds. J Clin Microbiol. 2013; 51:2608-16. https://pubmed.ncbi.nlm.nih.gov/23740727
20. Howard SJ, Lass-Flörl C, Cuenca-Estrella M et al. Determination of isavuconazole susceptibility of Aspergillus and Candida species by the EUCAST method. Antimicrob Agents Chemother. 2013; 57:5426-31. https://pubmed.ncbi.nlm.nih.gov/23959309
21. Arendrup MC, Howard S, Lass-Flörl C et al. EUCAST testing of Isavuconazole susceptibility in Aspergillus: comparison of results for Inoculum standardization using Conidium counting versus optical density. Antimicrob Agents Chemother. 2014; 58:6432-6. https://pubmed.ncbi.nlm.nih.gov/25136005
22. Gregson L, Goodwin J, Johnson A et al. In vitro susceptibility of Aspergillus fumigatus to isavuconazole: correlation with itraconazole, voriconazole, and posaconazole. Antimicrob Agents Chemother. 2013; 57:5778-80. https://pubmed.ncbi.nlm.nih.gov/24041890
23. Pfaller MA, Rhomberg PR, Wiederhold NP et al. In Vitro Activity of Isavuconazole against Opportunistic Fungal Pathogens from Two Mycology Reference Laboratories. Antimicrob Agents Chemother. 2018; 62 https://pubmed.ncbi.nlm.nih.gov/30061288
24. Jørgensen KM, Astvad KMT, Hare RK et al. EUCAST susceptibility testing of isavuconazole: MIC data for contemporary clinical mould and yeast isolates. Antimicrob Agents Chemother. 2019; https://pubmed.ncbi.nlm.nih.gov/30910898
25. Ruiz-Gaitán AC, Cantón E, Fernández-Rivero ME et al. Outbreak of Candida auris in Spain: A comparison of antifungal activity by three methods with published data. Int J Antimicrob Agents. 2019; 53:541-546. https://pubmed.ncbi.nlm.nih.gov/30769198
26. Kathuria S, Singh PK, Sharma C et al. Multidrug-Resistant Candida auris Misidentified as Candida haemulonii: Characterization by Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry and DNA Sequencing and Its Antifungal Susceptibility Profile Variability by Vitek 2, CLSI Broth Microdilution, and Etest Method. J Clin Microbiol. 2015; 53:1823-30. https://pubmed.ncbi.nlm.nih.gov/25809970
27. Larkin E, Hager C, Chandra J et al. The Emerging Pathogen Candida auris: Growth Phenotype, Virulence Factors, Activity of Antifungals, and Effect of SCY-078, a Novel Glucan Synthesis Inhibitor, on Growth Morphology and Biofilm Formation. Antimicrob Agents Chemother. 2017; 61 https://pubmed.ncbi.nlm.nih.gov/28223375
28. Desnos-Ollivier M, Bretagne S, Boullié A et al. Isavuconazole MIC distribution of 29 yeast species responsible for invasive infections (2015-2017). Clin Microbiol Infect. 2019; 25:634.e1-634.e4. https://pubmed.ncbi.nlm.nih.gov/30771532
29. Maertens JA, Raad II, Marr KA et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet. 2016; 387:760-9. https://pubmed.ncbi.nlm.nih.gov/26684607
30. Marty FM, Ostrosky-Zeichner L, Cornely OA et al. Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis. Lancet Infect Dis. 2016; 16:828-837. https://pubmed.ncbi.nlm.nih.gov/26969258
31. Desai A, Helmick M, Heo N, et al. Pharmacokinetics and bioequivalence of isavuconazole administered as isavuconazonium sulfate intravenous solution via nasogastric tube or orally in healthy subjects. Antimicrob Agent Chemother. 2021;65(9):1-9.
32. Arrieta AC, Segers H, Deville JG, et al. Safety and outcomes of isavuconazonium sulfate for the treatment of invasive aspergillosis of invasive mucormycosis in pediatric patients. Open Forum Infect Dis. 2023;10(Suppl 2):abstract 1699.
33. Crum NF. Coccidioidomycosis: a contemporary review. Infect Dis Ther. 2022;11:713-42.
34. Johnson RH, Sharma R, Kuran R, Fong I, Heidari A. Coccidioidomycosis: a review. J Investig Med. 2021;69:316-23.
35. Galgiani JN, Ampel NM, Catanzaro A, Johnson RH, Stevens DA, Williams PL. Practice guidelines for the treatment of coccidioidomycosis. Clin Infect Dis. 2000;30:658-61.
36. Galgiani JN, Ampel NM, Blair JE, et al. 2016 Infectious Diseases Society of America (IDSA) clinical practice guideline for the treatment of coccidioidomycosis. Clin Infect Dis. 2016;63(6):e112-46.
37. Heidari A, Quinlan M, Benjamin DJ, et al. Isavuconazole in the treatment of coccidioidal meningitis. Antimicrob Agent Chemother. 2019;63(3):1-4.
38. Heidari A, Sharma R, Shakir Q, et al. Isavuconazole in the treatment of chronic forms of coccidioidomycosis. Clin Infect Dis. 2023;76(12):2196-9.
423. Patterson TF, Thompson GR, Denning DW et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016; 63:e1-e60. Updates may be available at IDSA website at www.idsociety.org. https://pubmed.ncbi.nlm.nih.gov/27365388
424. Cornely OA, Arenz D, Vehreschild MD, et al. Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium. Lancet Infect Dis. 2019;19(12):e405-e421.
425. Pappas PG, Kauffman CA, Andes DR et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016; 62:e1-50. Updates may be available at IDSA website at www.idsociety.org. https://pubmed.ncbi.nlm.nih.gov/26679628
440. Panel on Opportunistic Infection in Adults and Adolescents with HIV. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America (Accessed May 8, 2024). Updates may be available at HIV.gov website https://clinicalinfo.hiv.gov/en/guidelines
More about isavuconazonium
- Check interactions
- Compare alternatives
- Reviews (2)
- Side effects
- Dosage information
- During pregnancy
- Drug class: azole antifungals
- En español