isavuconazonium

Absorption: Prodrug is rapidly converted to isavuconazole, the active component. 98% absorbed following oral administration. IV administration results in complete bioavailability.

Distribution: Extensively distributed.

Protein Binding: >99%

Metabolism/Excretion: Extensively metabolized by liver by the CYP3A4 and CYP3A5 isoenzymes; inactive metabolites are mostly renally eliminated. <1% excreted unchanged in urine.

Half-Life: 130 hr

Time/Action Profile ⬆ ⬇

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
PO	unknown	2 hr	unknown
IV	unknown	end of infusion	unknown

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Hypersensitivity;
Strong CYP3A4 inhibitors;
Familial short QT syndrome;
Strong CYP3A4 inducers;
OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

Severe hepatic impairment (use only if benefits outweigh risks; monitor carefully for adverse reactions);
Rep: Women of reproductive potential;
Pedi: Safety and effectiveness not established in children 1 yr (IV) or 6 yr and 16 kg (PO).

Adv. Reactions/Side Effects ⬆ ⬇

CV: peripheral edema, chest pain, hypotension

Derm: pruritus, rash, STEVENS-JOHNSON SYNDROME (SJS)

F and E: hypokalemia, hypomagnesemia

GI: ↑liver enzymes, constipation, diarrhea, nausea, vomiting, ↓appetite, dyspepsia

GU: renal failure

Local: injection site reactions

MS: back pain

Neuro: fatigue, headache, insomnia, anxiety, delirium

Resp: cough, dyspnea, respiratory failure

Misc: HYPERSENSITIVITY REACTIONS (INCLUDING ANAPHYLAXIS), infusion-related reactions

Interactions ⬆ ⬇

Drug-drug:

Strong CYP3A4 inhibitors, including ketoconazole or high-dose ritonavir, ↑ levels and risk of toxicity; concurrent use contraindicated.
Strong CYP3A4 inducers, including long-acting barbiturates, carbamazepine, or rifampin, may ↓ levels and effectiveness; concurrent use contraindicated.
Lopinavir/ritonavir significantly ↑ levels and risk of toxicity; concurrent use should be undertaken with caution.
Isavuconazonium ↓ levels and effectiveness of lopinavir/ritonavir.
Isavuconazonium ↑ levels and risk of toxicity of atorvastatin, cyclosporine, digoxin, midazolam, mycophenolate, sirolimus, and tacrolimus; undertake concurrent use with caution, monitoring drug effects and making adjustments if necessary.
↓levels and effectiveness of bupropion; bupropion dose may need to be ↑ but should not exceed maximum recommended dose.

Drug-Natural Products:

St. John's wort↓ levels and effectiveness; concurrent use contraindicated.

Route/Dosage ⬆ ⬇

PO IV (Adults ≥18 yr): Loading dose: 372 mg isavuconazonium (PO as either two 186 mg capsules or five 74.5 mg capsules; equivalent to 200 mg isavuconazole) every 8 hr for six doses; Maintenance dose: 372 mg isavuconazonium (PO as either two 186 mg capsules or five 74.5 mg capsules; equivalent to 200 mg isavuconazole) once daily starting 12–24 hr after last loading dose.
IV (Children 3–<18 yr and ≥37 kg): Loading dose: 372 mg isavuconazonium (equivalent to 200 mg isavuconazole) every 8 hr for six doses; Maintenance dose: 372 mg isavuconazonium (equivalent to 200 mg isavuconazole) once daily starting 12–24 hr after last loading dose.
IV (Children 3–<18 yr and <37 kg): Loading dose: 10 mg/kg isavuconazonium every 8 hr for six doses; Maintenance dose: 10 mg/kg isavuconazonium once daily starting 12–24 hr after last loading dose.
IV (Children 1–<3 yr and <18 kg): Loading dose: 15 mg/kg isavuconazonium every 8 hr for six doses; Maintenance dose: 15 mg/kg isavuconazonium once daily starting 12–24 hr after last loading dose.
PO (Children 6–<18 yr and ≥32 kg): Loading dose: 372 mg isavuconazonium (five 74.5 mg capsules; equivalent to 200 mg isavuconazole) every 8 hr for six doses; Maintenance dose: 372 mg isavuconazonium (five 74.5 mg capsules; equivalent to 200 mg isavuconazole) once daily starting 12–24 hr after last loading dose.
PO (Children 6–<18 yr and 25–<32 kg): Loading dose: 298 mg isavuconazonium (four 74.5 mg capsules; equivalent to 160 mg isavuconazole) every 8 hr for six doses; Maintenance dose: 298 mg isavuconazonium (four 74.5 mg capsules; equivalent to 160 mg isavuconazole) once daily starting 12–24 hr after last loading dose.
PO (Children 6–<18 yr and 18–<25 kg): Loading dose: 223.5 mg isavuconazonium (three 74.5 mg capsules; equivalent to 120 mg isavuconazole) every 8 hr for six doses; Maintenance dose: 223.5 mg isavuconazonium (three 74.5 mg capsules; equivalent to 120 mg isavuconazole) once daily starting 12–24 hr after last loading dose.
PO (Children 6–<18 yr and 16–<18 kg): Loading dose: 149 mg isavuconazonium (two 74.5 mg capsules; equivalent to 80 mg isavuconazole) every 8 hr for six doses; Maintenance dose: 149 mg isavuconazonium (two 74.5 mg capsules; equivalent to 80 mg isavuconazole) once daily starting 12–24 hr after last loading dose.

Availability ⬆ ⬇

Capsules: 74.5 mg isavuconazonium (equivalent to 40 mg isavuconazole); 186 mg isavuconazonium (equivalent to 100 mg isavuconazole)
Lyophilized powder for injection: 372 mg isavuconazonium (equivalent to 200 mg isavuconazole)/vial

Assessment ⬆ ⬇

Monitor signs and symptoms of infection (fever, cough) periodically during therapy.
Obtain specimens for culture and sensitivity prior to therapy. First dose may be given before receiving results.
Monitor for signs and symptoms of infusion-related reactions (hypotension, dyspnea, chills, dizziness, paresthesia, hypoesthesia) periodically during therapy. Discontinue infusion if symptoms occur.
Monitor skin for hypersensitivity reactions during therapy such as SJS.

Lab Test Considerations:

Verify negative pregnancy test before starting therapy. Monitor LFTs, BUN, serum creatinine, and electrolytes at baseline and periodically during therapy. If severe hepatic impairment occurs, discontinue therapy.

Implementation ⬆ ⬇

Oral and IV formulations are bioequivalent; may be used interchangeably. Loading dose is not needed when switching.
PO: Administer without regard to food. DNC: Swallow capsule whole; do not open, dissolve, crush, or chew.
- To administer via NG tube, reconstitute one vial isavuconazonium for injection (equivalent to 200 mg isavuconazonium) with 5 mL of water for injection. Withdraw the entire contents (5 mL) of vial using a syringe and needle. Discard the needle and cap the syringe. To administer, remove cap from syringe containing the reconstituted solution and connect the syringe to NG tube to deliver dose. After administering, administer three 5 mL rinses to NG tube with water. Administer reconstituted solution via NG tube within 1 hr of reconstitution. Do not administer capsules via NG tube.

IV Administration:

Reconstitution: Reconstitute by adding 5 mL sterile water to vial. Shake gently to dissolve powder completely. Solution should be clear and colorless; do not administer solutions that are discolored or contain particulate matter. Solution is stable for 1 hr at room temperature.
Intermittent Infusion: Diluent: Remove 5 mL of reconstituted solution from vial and add to 250 mL 0.9% NaCl or D5W.Concentration: 1.5 mg isavuconazonium/mL. Diluted solution may show visible translucent to white particulates; removed with in-line filter. Roll bag to mix gently; avoid shaking. Solution is stable if infused at room temperature within 6 hr; may refrigerate for up to 24 hr; do not freeze. Flush line with 0.9% NaCl or D5W prior to and following infusion.
Rate: Infuse over at least 1 hr to minimize infusion-related reactions. Infuse through a 0.2–1.2 micron in-line filter. Do not administer as a bolus injection.

Patient/Family Teaching ⬆ ⬇

Explain purpose and side effects of isavuconazonium to patient. Instruct patient to take isavuconazonium as directed. Do not stop taking isavuconazonium without consulting heath care professional. If missed dose, take as soon as remembered or resume regular dose if almost time; do not take extra dose. Advise patient to read Patient Information before starting and with each Rx refill in case of changes.
Advise patient to notify health care professional promptly of signs and symptoms of liver disease (itchy skin, nausea, vomiting, yellowing of eyes, dark urine, feeling very tired, stomach pain), infusion-related reactions (flu-like symptoms, dizziness, numb/tingling skin), or hypersensitivity reactions (blistering, peeling, red skin rash) occur.
Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications.
Rep: May cause fetal harm. Advise females of reproductive potential to use effective contraception during therapy and for 28 days after final dose and to avoid breastfeeding during therapy. Advise patient to notify health care professional if pregnancy is planned or suspected.
Emphasize the importance of lab tests to monitor for side effects during therapy.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇