Isavuconazonium sulfate (Isavuconazole)

Indications

Isavuconazonium sulfate (Isavuconazole) is used for: Invasive Aspergillosis, Invasive Mucormycosis

Adult Dose

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 Hepatic impairment Mild or moderate: No dose adjustment required Severe: Not studied

Child Dose

<18 years: Safety and efficacy not established

Renal Dose

Renal impairment Mild, moderate, or severe (including ESRD): No dose adjustment required

Administration

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

Contra Indications

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

Precautions

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-Lactation

Pregnancy Based on findings from animal studies, fetal harm may occur when administered to pregnant women No human data available on use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes Animal studies In animal reproduction studies, perinatal mortality was increased in the offspring of pregnant rats dosed orally with isavuconazonium sulfate at 90 mg/kg/day during pregnancy through the weaning period In animal studies when isavuconazonium chloride was administered by oral gavage to pregnant rats and rabbits during organogenesis at exposures corresponding to less than the human maintenance dose, increases in the incidences of multiple skeletal abnormalities, including rudimentary cervical ribs and fused zygomatic arches, were observed Contraception Advise female patients of reproductive potential to use effective contraception during treatment and for 28 days after the final dose Lactation Isavuconazole was present in the milk of lactating rats following IV administration Thus, drug may be present in human milk Therefore, breastfeeding should be discontinued during treatment

Interactions

Adverse Effects

Side effects of Isavuconazonium sulfate (Isavuconazole) : >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%)

Mechanism of Action

Triazole antifungal agent; isavuconazole is the active moiety of the prodrug isavuconazonium sulfate