Dosing and uses of Cresemba, isavuconazole (isavuconazonium sulfate)
Adult dosage forms and strengths
capsule
- 186mg isavuconazonium sulfate (equivalent to 100mg isavuconazole)
injection, lyophilized powder for reconstitution
- 372mg isavuconazonium sulfate (equivalent to 200mg isavuconazole)
Invasive Aspergillosis
Indicated for invasive aspergillosis
Has activity against most strains of the following microorganisms, both in vitro and in clinical infection: Aspergillus flavus, Aspergillus fumigatus, and Aspergillus niger
Initial: 372 mg PO/IV q8hr x6 doses (48 hr)
Maintenance: 372 mg PO/IV qDay
Invasive Mucormycosis
Indicated for invasive mucormycosis caused by Mucorales fungi such as Rhizopus oryzae and Mucormycetes species
Initial: 372 mg PO/IV q8hr x6 doses (48 hr)
Maintenance: 372 mg PO/IV qDay
Dosage modifications
Renal impairment
- Mild, moderate, or severe (including ESRD): No dose adjustment required
Hepatic impairment
- Mild or moderate: No dose adjustment required
- Severe: Not studied
Pediatric dosage forms and strengths
<18 years: Safety and efficacy not established
Cresemba, isavuconazole (isavuconazonium sulfate) adverse (side) effects
>10%
Nausea (27.6%)
Vomiting (24.9%)
Diarrhea (23.7%)
Hypokalemia (19.1%)
Elevated liver tests (17.1%)
Dyspnea (17.1%)
Abdominal pain (16.7%)
Headache (16.7%)
Peripheral edema (15.2%)
Constipation (14%)
Fatigue (10.5%)
Insomnia (10.5%)
Back pain (10.1%)
Renal failure (10.1%)
1-10%
Chest pain (8.9%)
Decreased appetite (8.6%)
Delirium (8.6%)
Rash (8.6%)
Pruritus (8.2%)
Hypotension (8.2%)
Anxiety (8.2%)
Acute respiratory failure (7.4%)
Injection site reaction (6.2%)
Dyspepsia (6.2%)
Hypomagnesemia (5.4%)
Cardiac disorders: Atrial fibrillation, atrial flutter, bradycardia, reduced QT interval on electrocardiogram, palpitations, supraventricular extrasystoles, supraventricular tachycardia, ventricular extrasystoles, cardiac arrest (<5%)
Nervous system disorders: Convulsion, dysgeusia, encephalopathy, hypoesthesia, migraine, peripheral neuropathy, paraesthesia, somnolence, stupor, syncope, tremor (<5%)
Psychiatric disorders: Confusion, hallucination, depression (<5%)
Renal and urinary disorders: Hematuria, proteinuria (<5%)
Respiratory, thoracic, and mediastinal disorders: Bronchospasm, tachypnea (<5%)
Warnings
Contraindications
Known hypersensitivity
Strong CYP3A4 inhibitors; coadministration with strong CYP3A4 inhibitors can significantly increase the plasma concentration of isavuconazole
Strong CYP3A4 inducers; coadministration with strong CYP3A4 inducers can significantly decrease the plasma concentration of isavuconazole
Familial short QT syndrome; isavuconazole shortens the QTc interval in a concentration-related manner
Cautions
Hepatic adverse drug reactions (eg, elevated ALT, AST, alkaline phosphatase, total bilirubin) reported; the elevations in liver-related laboratory tests were generally reversible and did not require discontinuation of drug; cases of more severe hepatic adverse drug reactions, including hepatitis, cholestasis, or hepatic failure including death, have been reported in patients with serious underlying medical conditions (eg, hematologic malignancy) during treatment with azole antifungal agents
Infusion-related reactions, including hypotension, dyspnea, chills, dizziness, paresthesia, and hypoesthesia, were reported; discontinue the infusion if these reaction occur
Serious hypersensitivity and severe skin reactions (eg, anaphylaxis, Stevens-Johnson syndrome) have been reported during treatment with other azole antifungal agents
May cause fetal harm when administered to a pregnant woman; should be used during pregnancy only if the potential benefit to the patient outweighs the risk to the fetus
Pregnancy and lactation
Pregnancy
Pregnancy category: C
Based on animal data, predicted to have the potential for increasing the risk of adverse developmental outcomes above background risk
Perinatal mortality was significantly increased in the offspring of pregnant rats dosed orally with isavuconazonium sulfate at 90 mg/kg/day (less than half the maintenance human dose based on AUC comparisons) during pregnancy through the weaning period
Lactation
Do not breast-feed
Isavuconazole is excreted in the milk of lactating rats following intravenous administration
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Cresemba, isavuconazole (isavuconazonium sulfate)
Mechanism of action
Triazole antifungal agent; isavuconazole is the active moiety of the prodrug isavuconazonium sulfate
Absorption
Absolute bioavailability: 98%
Peak plasma concentration: 7,499 ng/mL (2 capsules); 20,028 (6 capsules)
Peak plasma time: 3 hr (2 capsules); 4 hr (6 capsules)
AUC: 121,402 hr ng/mL (2 capsules); 352,805 hr•ng/mL (6 capsules)
Distribution
Protein bound: >99%
Vd: 450 L
Metabolism
Isavuconazonium sulfate is rapidly hydrolyzed in blood to isavuconazole by esterases, predominately by butylcholinesterase to isavuconazole
Isavuconazole is a substrate of cytochrome P450 enzymes 3A4 and 3A5
Except for the active moiety isavuconazole, no individual metabolite observed with an AUC >10% of drug-related materiaL
In vivo studies indicate that CYP3A4, CYP3A5, and subsequently uridine diphosphate-glucuronosyltransferases (UGTs) are involved in the metabolism of isavuconazole
Elimination
Half-life: 130 hr
Excretion: 46.1% feces; 45.5% urine
Administration
IV Compatibilities
0.9% NaCl injection
D5W injection
IV Preparation
Reconstitute lyophilized powder in viaL
- Reconstitute 1 vial by adding 5 mL sterile water for injection
- Gently shake to dissolve the powder completely
- Visually inspect the reconstituted solution for particulate matter and discoloration; reconstituted solution should be clear and free of visible particulate
Further dilution
- Remove 5 mL of the reconstituted solution from the vial and add it to an infusion bag containing 250 mL (approximately 1.5 mg/mL isavuconazonium sulfate) of compatible diluent
- The diluted solution may show visible translucent-to-white particulates of isavuconazole (which will be removed by in-line filtration)
- Use gentle mixing or roll bag to minimize the formation of particulates
- Avoid unnecessary vibration or vigorous shaking of the solution
- Apply in-line filter with a microporous membrane pore size of 0.2 - 1.2 micron and in-line filter reminder sticker to the infusion bag
IV Administration
Do not use a pneumatic transport system
Complete IV administration within 6 hr of dilution at room temperature (or immediately store refrigerated, see Storage)
IV formulation must be administered via an infusion set with an in-line filter (pore size 0.2-1.2 micron)
Infuse over a minimum of 1 hr in 250 mL of a compatible diluent, to reduce the risk for infusion-related reactions
Do not administer as an intravenous bolus injection
Do not infuse with other intravenous medications
Flush IV lines with 0.9% NaCl injection or D5W prior to and after infusion
Oral Administration
Switching between IV and oral formulations is acceptable as bioequivalence has been demonstrated
Loading dose is not required when switching between formulations
Swallow oral capsules whole; do not chew, crush, dissolve, or open the capsules
Can be taken with or without food
Storage
Reconstituted solution: May be stored below 25°C for maximum 1 hr prior to preparation of the patient infusion solution
Diluted IV solution
- If unable to administer IV diluted solution within 6 hr of preparation, immediately refrigerate (2-8°C [36-46°F]) the infusion solution after dilution and complete the infusion within 24 hr
- Do not freeze the infusion solution
