Isavuconazonium Sulfate

Pronunciation

(eye sa vue koe na ZOE nee um sul FATE)

Index Terms

• BAL8557
• Isavuconazole

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Cresemba: 186 mg [contains disodium edta]

Solution Reconstituted, Intravenous:

Cresemba: 372 mg (1 ea)

Brand Names: U.S.

• Cresemba

Pharmacologic Category

• Antifungal Agent, Azole Derivative
• Antifungal Agent, Oral
• Antifungal Agent, Parenteral

Pharmacology

Isavuconazonium sulfate is a prodrug that is rapidly hydrolyzed in the blood to active isavuconazole. Isavuconazole inhibits the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14-alpha-demethylase. This enzyme is responsible for the conversion of lanosterol to ergosterol. An accumulation of methylated sterol precursors and a depletion of ergosterol within the fungal cell membrane weakens the membrane structure and function.

Distribution

V_ss: IV: ~450 L

Metabolism

Metabolism: Isavuconazonium sulfate (prodrug) is rapidly hydrolyzed in the blood by esterases to active isavuconazole and an inactive cleavage product. Isavuconazole is metabolized by CYP3A4, CYP 3A5 and UGT.

Excretion

Oral: 46.1% (feces), 45.5% (urine)

Time to Peak

Oral: 2 to 3 hours

Half-Life Elimination

IV: 130 hours

Protein Binding

>99% (primarily to albumin)

Special Populations: Hepatic Function Impairment

Patients with mild and moderate hepatic impairment had 40% and 48% lower isavuconazole Cl values, respectively, compared with healthy subjects.

Special Populations: Race

Chinese subjects were found to have on average a 40% lower clearance compared with Western subjects (1.6 L/hour for Chinese subjects compared with 2.6 L/hour for Western subjects) and therefore approximately 50% higher AUC than Western subjects.

Use: Labeled Indications

Aspergillosis: Treatment of invasive aspergillosis in adults

Mucormycosis: Treatment of invasive mucormycosis in adults

Contraindications

Hypersensitivity to isavuconazonium sulfate (eg, isavuconazole) or any component of the formulation; concurrent use of strong CYP3A4 inhibitors (eg, ketoconazole, high-dose ritonavir [400 mg every 12 hours]); concurrent use of strong CYP3A4 inducers (eg, rifampin, carbamazepine, St. John’s wort, long acting barbiturates); familial short QT syndrome

Dosing: Adult

Note: Dosage expressed as milligrams of isavuconazonium sulfate; switching between the intravenous (IV) and oral formulations of isavuconazonium sulfate is acceptable; for maintenance dosing, it is not necessary to restart dosing with the initial dose regimen when switching between formulations.

Aspergillosis, invasive:

IV: Initial: 372 mg (isavuconazole 200 mg) every 8 hours for 6 doses; Maintenance: 372 mg (isavuconazole 200 mg) once daily. Start maintenance dose 12 to 24 hours after the last loading dose.

Oral: Initial: 372 mg (200 mg isavuconazole) every 8 hours for 6 doses; Maintenance: 372 mg (isavuconazole 200 mg) once daily. Start maintenance dose 12 to 24 hours after the last loading dose.

Mucormycosis, invasive:

IV: Initial: 372 mg (isavuconazole 200 mg) every 8 hours for 6 doses; Maintenance: 372 mg (isavuconazole 200 mg) once daily. Start maintenance dose 12 to 24 hours after the last loading dose.

Oral: Initial: 372 mg (isavuconazole 200 mg) every 8 hours for 6 doses; Maintenance: 372 mg (isavuconazole 200 mg) once daily. Start maintenance dose 12 to 24 hours after the last loading dose.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment necessary.

Dosing: Hepatic Impairment

Mild or moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary.

Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use with caution.

Reconstitution

Reconstitute 1 vial of isavuconazonium with 5 mL SWFI. Shake gently to dissolve. The reconstituted solution may be stored below 25°C for a maximum of 1 hour prior to preparation of the admixed solution. Remove 5 mL of the reconstituted solution from the vial and add it to an infusion bag containing 250 mL (approximately isavuconazonium sulfate 1.5 mg/mL) of NS or D5W. The diluted solution may show visible translucent to white particulates of isavuconazole (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. Do not use a pneumatic transport system. Apply in-line filter with a microporous membrane pore size of 0.2 to 1.2 micron and in-line filter reminder sticker to the infusion bag. The IV administration should be completed within 6 hours at 20°C to 25°C (68°F to 77°F) . If this is not possible, immediately refrigerate (2°C to 8°C [36°F to 46°F]) the admixed solution and complete the infusion within 24 hours.

Administration

IV: Infuse over a minimum of 1 hour; must be administered via an infusion set with an in-line filter (pore size 0.2 to 1.2 micron). Do not administer as an IV bolus injection.

Oral: Swallow capsules whole;. do not chew, crush, dissolve, or open. Administer with or without food.

Compatibility

Stable in NS, D₅W

Storage

Capsules: Store at 20°C to 25°C (68°F to 77°F) in the original packaging to protect from moisture; excursions are permitted between 15°C and 30°C (59°F and 86°F).

IV: Store intact vials at 2°C to 8°C (36°F to 46°F). Following reconstitution of the vial with SWFI, use the solution immediately, or stored below 25°C for a maximum of 1 hour prior to preparation of the admixed solution in NS or D5W. The admixed infusion solution should be kept for not more than 6 hours at (20°C to 25°C [68°F to 77°F]) or 24 hours at 2°C to 8°C (36°F to 46°F) prior to use. Do not freeze.

Drug Interactions

AmLODIPine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of AmLODIPine. Monitor therapy

Amodiaquine: CYP2C8 Inhibitors may increase the serum concentration of Amodiaquine. Avoid combination

Amphotericin B: Antifungal Agents (Azole Derivatives, Systemic) may diminish the therapeutic effect of Amphotericin B. Monitor therapy

Apixaban: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Apixaban. Monitor therapy

Aprepitant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Aprepitant. Avoid combination

ARIPiprazole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

Asunaprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Asunaprevir. Avoid combination

Avanafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avanafil. Management: The maximum avanafil adult dose is 50 mg per 24-hour period when used together with a moderate CYP3A4 inhibitor. Patients receiving such a combination should also be monitored more closely for evidence of adverse effects. Consider therapy modification

Blonanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Blonanserin. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Bosentan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy

Bosutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bosutinib. Avoid combination

Brexpiprazole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Brexpiprazole. Management: The brexpiprazole dose should be reduced to 25% of usual if used together with both a moderate CYP3A4 inhibitor and a strong or moderate CYP2D6 inhibitor, or if a moderate CYP3A4 inhibitor is used in a CYP2D6 poor metabolizer. Monitor therapy

Bromocriptine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bromocriptine. Management: The bromocriptine dose should not exceed 1.6 mg daily with use of a moderate CYP3A4 inhibitor. The Cycloset brand specifically recommends this dose limitation, but other bromocriptine products do not make such specific recommendations. Consider therapy modification

Budesonide (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Systemic). Avoid combination

Budesonide (Topical): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Topical). Management: Per US prescribing information, avoid this combination. Canadian product labeling does not recommend strict avoidance. If combined, monitor for excessive glucocorticoid effects as budesonide exposure may be increased. Consider therapy modification

BuPROPion: Isavuconazonium Sulfate may decrease the serum concentration of BuPROPion. Monitor therapy

Cannabis: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be increased. Monitor therapy

Cilostazol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in adult patients who are also receiving moderate inhibitors of CYP3A4. Consider therapy modification

Cobimetinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cobimetinib. Management: Avoid the concomitant use of cobimetinib and moderate CYP3A4 inhibitors. If concurrent short term (14 days or less) use cannot be avoided, reduce the cobimetinib dose to 20 mg daily. Avoid combination

Colchicine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Colchicine. Management: Reduce colchicine dose as directed when using with a moderate CYP3A4 inhibitor, and increase monitoring for colchicine-related toxicity. Use extra caution in patients with impaired renal and/or hepatic function. Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May decrease serum concentrations of the active metabolite(s) of Isavuconazonium Sulfate. Specifically, CYP3A4 Inducers (Strong) may decrease isavuconazole serum concentrations. Avoid combination

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase serum concentrations of the active metabolite(s) of Isavuconazonium Sulfate. Specifically, CYP3A4 Inhibitors (Strong) may increase isavuconazole serum concentrations. Management: Combined use is considered contraindicated per US labeling. Lopinavir/ritonavir (and possibly other uses of ritonavir doses less than 400 mg every 12 hours) is treated as a possible exception to this contraindication despite strongly inhibiting CYP3A4. Avoid combination

CYP3A4 Substrates: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of CYP3A4 Substrates. Exceptions: Alitretinoin (Systemic); Praziquantel; Vinorelbine. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dapoxetine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dapoxetine. Management: The dose of dapoxetine should be limited to 30 mg/day when used together with a moderate inhibitor of CYP3A4. Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Digoxin: Isavuconazonium Sulfate may increase the serum concentration of Digoxin. Monitor therapy

Dofetilide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dofetilide. Monitor therapy

Domperidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Domperidone. Avoid combination

DOXOrubicin (Conventional): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to moderate CYP3A4 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Dronabinol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dronabinol. Monitor therapy

Eletriptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eletriptan. Management: The use of eletriptan within 72 hours of a moderate CYP3A4 inhibitor should be avoided. Consider therapy modification

Eliglustat: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eliglustat. Management: Use should be avoided under some circumstances. See full drug interaction monograph for details. Consider therapy modification

Eplerenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eplerenone. Management: When used concomitantly with moderate inhibitors of CYP3A4, eplerenone dosing recommendations vary by indication and international labeling. See full drug interaction monograph for details. Consider therapy modification

Everolimus: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Consider therapy modification

FentaNYL: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of FentaNYL. Management: Monitor patients closely for several days following initiation of this combination, and adjust fentanyl dose as necessary. Consider therapy modification

Flibanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Flibanserin. Avoid combination

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

GuanFACINE: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of GuanFACINE. Management: Reduce the guanfacine dose by 50% when initiating this combination. Consider therapy modification

Halofantrine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Halofantrine. Consider therapy modification

HYDROcodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of HYDROcodone. Monitor therapy

Ibrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ibrutinib. Management: If a moderate CYP3A inhibitor must be used, consider reducing the dose of ibrutinib to 140mg daily and monitor closely for signs of toxicity. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ifosfamide: CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. Monitor therapy

Imatinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Imatinib. Monitor therapy

Ivabradine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivabradine. Avoid combination

Ivacaftor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivacaftor. Management: Ivacaftor dose reductions are required; consult prescribing information for specific age- and weight-based recommendations. Consider therapy modification

Lomitapide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lomitapide. Avoid combination

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Lurasidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lurasidone. Management: U.S. labeling: start at 20 mg/day and limit to max of 80 mg/day with moderate CYP3A4 inhibitor. Canadian labeling: limit to max of 40 mg/day with moderate CYP3A4 inhibitor; avoid concomitant use of grapefruit products. Consider therapy modification

Mirodenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Mirodenafil. Monitor therapy

Mycophenolate: Isavuconazonium Sulfate may increase the serum concentration of Mycophenolate. Monitor therapy

Naloxegol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Naloxegol. Avoid combination

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

NiMODipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of NiMODipine. Monitor therapy

Olaparib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Olaparib. Management: Avoid use of moderate CYP3A4 inhibitors in patients being treated with olaparib. If such concurrent use cannot be avoided, the dose of olaparib should be reduced to 200 mg twice daily. Avoid combination

OxyCODONE: CYP3A4 Inhibitors (Moderate) may enhance the adverse/toxic effect of OxyCODONE. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of OxyCODONE. Serum concentrations of the active metabolite Oxymorphone may also be increased. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Pimecrolimus: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of Pimecrolimus. Monitor therapy

Pimozide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pimozide. Avoid combination

Propafenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Propafenone. Monitor therapy

Ranolazine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ranolazine. Management: Limit the ranolazine adult dose to a maximum of 500 mg twice daily in patients concurrently receiving moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil, erythromycin, etc.). Consider therapy modification

Saccharomyces boulardii: Antifungal Agents (Systemic, Oral) may diminish the therapeutic effect of Saccharomyces boulardii. Avoid combination

Salmeterol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Salmeterol. Monitor therapy

SAXagliptin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of SAXagliptin. Monitor therapy

Sildenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sildenafil. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Simeprevir. Avoid combination

Sonidegib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sonidegib. Management: Avoid concomitant use of sonidegib and moderate CYP3A4 inhibitors when possible. When concomitant use cannot be avoided, limit CYP3A4 inhibitor use to less than 14 days and monitor for sonidegib toxicity (particularly musculoskeletal adverse reactions). Consider therapy modification

St John's Wort: May decrease serum concentrations of the active metabolite(s) of Isavuconazonium Sulfate. Specifically, St Johns Wort may decrease isavuconazole serum concentrations. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Suvorexant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Suvorexant. Consider therapy modification

Tetrahydrocannabinol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

Ticagrelor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ticagrelor. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Tolvaptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tolvaptan. Avoid combination

Trabectedin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Trabectedin. Avoid combination

Udenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Udenafil. Monitor therapy

Ulipristal: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ulipristal. Management: This is specific for when ulipristal is being used for signs/symptoms of uterine fibroids (Canadian indication). When ulipristal is used as an emergency contraceptive, patients receiving this combination should be monitored for ulipristal toxicity. Avoid combination

Venetoclax: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification

Vilazodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vilazodone. Monitor therapy

Vindesine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vindesine. Monitor therapy

Zopiclone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zopiclone. Management: The starting adult dose of zopiclone should not exceed 3.75 mg if combined with a moderate CYP3A4 inhibitor. Monitor patients for signs and symptoms of zopiclone toxicity if these agents are combined. Consider therapy modification

Zuclopenthixol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zuclopenthixol. Monitor therapy

Adverse Reactions

Frequency not always defined.

>10%:

Cardiovascular: Peripheral edema (11% to 15%)

Central nervous system: Headache (17%), fatigue (11%), insomnia (11%)

Endocrine & metabolic: Hypokalemia (14% to 19%)

Gastrointestinal: Nausea (26% to 28%), vomiting (25%), diarrhea (22% to 24%), abdominal pain (17%), constipation (13% to 14%)

Hepatic: Increased liver enzymes (16% to 17%)

Respiratory: Dyspnea (12% to 17%), cough (12%)

1% to 10%:

Cardiovascular: Chest pain (9%), hypotension (8%), atrial fibrillation (<5%), atrial flutter (<5%), bradycardia (<5%), cardiac arrest (<5%), catheter site thrombosis (<5%), extrasystoles (<5%), palpitations (<5%), shortened QT interval (<5%), supraventricular extrasystole (<5%), supraventricular tachycardia (<5%), syncope (<5%), thrombophlebitis (<5%), ventricular premature contractions (<5%)

Central nervous system: Delirium (9%), anxiety (8%), brain disease (<5%), chills (<5%), confusion (<5%), convulsions (<5%), depression (<5%), drowsiness (<5%), falling (<5%), hallucination (<5%), hypoesthesia (<5%), malaise (<5%), migraine (<5%), peripheral neuropathy (<5%), stupor (<5%), vertigo (<5%), dizziness, hypoesthesia, paresthesia

Dermatologic: Skin rash (9%), pruritus (8%), alopecia (<5%), dermatitis (<5%), erythema (<5%), exfoliative dermatitis (<5%), urticaria (<5%)

Endocrine & metabolic: Hypomagnesemia (5%), hypoalbuminemia (<5%), hypoglycemia (<5%), hyponatremia (<5%)

Gastrointestinal: Decreased appetite (9%), dyspepsia (6%), abdominal distention (<5%), cholecystitis (<5%), cholelithiasis (<5%), cholestasis (<5%), dysgeusia (<5%), gastritis (<5%), gingivitis (<5%), stomatitis (<5%)

Genitourinary: Hematuria (<5%), proteinuria (<5%)

Hematologic & oncologic: Agranulocytosis (<5%), leukopenia (<5%), pancytopenia (<5%), petechia (<5%)

Hepatic: Hepatitis (<5%), hepatomegaly (<5%), increased serum ALT (>3x ULN ≤4%; >10x ULN ≤1%), increased serum AST (>3x ULN ≤4%; >10x ULN ≤1%), hepatic failure, increased serum transaminases

Hypersensitivity: Hypersensitivity (<5%)

Local: Injection site reaction (6%)

Neuromuscular & Skeletal: Back pain (10%), myositis (<5%), neck pain (<5%), ostealgia (<5%), tremor (<5%)

Ophthalmic: Optic neuropathy (<5%)

Otic: Tinnitus (<5%)

Respiratory: Acute respiratory tract failure (7%), bronchospasm (<5%), tachypnea (<5%)

Warnings/Precautions

Concerns related to adverse effects:

• Hepatic effects: Severe reactions (hepatic failure [including fatalities], hepatitis, and cholestasis) have been reported in patients with serious underlying medical conditions (eg, hematologic malignancy). Other reactions (elevations in AST, ALT, alkaline phosphatase and total bilirubin) have also been reported; these elevations are generally reversible and do not require discontinuation of therapy. Monitor liver function tests at baseline and periodically during therapy. If abnormal liver function tests develop, monitor closely for development of severe hepatic reactions. Discontinue therapy if clinical signs and symptoms of liver disease develop.

• Hypersensitivity: Serious hypersensitivity (eg, anaphylaxis) and severe skin reactions (eg, Stevens-Johnson syndrome) have been reported with other azole antifungal agents. Discontinue if a severe skin reaction occurs. There is no information regarding cross-sensitivity between isavuconazonium sulfate and other azoles. Use with caution in patients with hypersensitivity reactions to other azoles.

Disease-related concerns:

• Hepatic impairment: Use with caution and monitor for adverse effects in patients with severe hepatic impairment (Child-Pugh class C).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Drug particulates: Following dilution for IV infusion, may form precipitate from the insoluble isavuconazole. Use an infusion set with an in-line filter (pore size 0.2 to 1.2 micron) for IV administration.

• Infusion-related reactions: Infusion reactions (eg, hypotension, dizziness, chills, dyspnea, paresthesia and hypoesthesia) have been reported during IV administration. Discontinue the infusion if these reactions occur.

Monitoring Parameters

Hypersensitivity reactions with initial doses, liver function tests (eg AST, ALT, alkaline phosphatase, total bilirubin) at baseline and periodically during therapy. Infusion-related reactions (eg hypotension, dyspnea, chills, dizziness, paresthesias, hypoesthesia) during IV infusion.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Based on animal data, isavuconazonium sulfate may have the potential to increase the risk of adverse developmental events if used in pregnant women.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience back pain, abdominal pain, cough, loss of strength and energy, constipation, headache, diarrhea, nausea, vomiting, lack of appetite, or insomnia. Have patient report immediately to prescriber signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, or weight gain), signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), angina, confusion, shortness of breath, swelling of arms or legs, signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) or signs of infusion-related reactions (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.