Isavuconazole : Indication, Adult Dose, MOA, Drug Interactions, Contraindications and more

 

Isavuconazole (isavuconazonium sulfate) is an antifungal agent used in the treatment of invasive aspergillosis and mucormycosis in adults.

Adult Dosage: 

Aspergillosis (invasive)

  Oral/IV 

• Loading dose: 372 mg Isavuconazonium sulfate for every 8 hours for 6 doses (48 hours)

• Maintenance dose: 372 mg Isavuconazonium sulfate OD

- Initiate maintenance dose 12– 24 hours after the last loading dose.

- Treatment duration is highly dependent on the degree/duration of immunosuppression, disease site, and evidence of disease improvement; minimum duration is 6–12 weeks.

Mucormycosis (invasive)

Oral/IV

• Loading dose: 372 mg Isavuconazonium sulfate for every 8 hours for 6 doses (48 hours)

• Maintenance dose: 372 mg Isavuconazonium sulfate OD

- Initiate maintenance dose 12–24 hours after the last loading dose.

Dosage Adjustments

Hepatic Impairment

• Mild-to-moderate (Child–Pugh class A or B): No dose adjustment is necessary.
• Severe impairment (Child–Pugh class C): Safety and efficacy is not established; use only when benefits outweigh the risk.

Renal Impairment

No dose adjustment is necessary.

Mechanism of action:

Isavuconazonium sulfate is the prodrug of Isavuconazole; it inhibits the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome P450 dependent enzyme lanosterol 14-alpha-demethylase. An accumulation of methylated sterol precursors and a depletion of ergosterol within the fungal cell membrane weakens the membrane structure and function.

Drug Interactions:

• Isavuconazonium sulfate will increase the level or effect of venetoclax; concomitant use should be avoided.

• Dichlorphenamide and isavuconazonium sulfate both decrease serum potassium levels; concomitant use should be avoided and use should be monitored.

• Coadministration of Isavuconazonium with strong CYP3A4 inhibitors, such as ketoconazole and high-dose ritonavir, or strong CYP3A4 inducers, such as rifampin, carbamazepine, St John’s wort, or long-acting barbiturates, should be avoided.

General Considerations

• IV preparation of lyophilized powder in the 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. The reconstituted solution should be clear and free of visible particulate. For 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: Complete IV administration within 6 hour of dilution at room temperature; IV formulation must be administered via an infusion set with an in-line filter (pore size 0.2-1.2 micron). Do not use a pneumatic transport system.

• Infuse over a minimum of 1 hour in 250 mL of a compatible diluent, to reduce the risk for infusion-related reactions.

• Do not administer as an IV bolus injection or with any other IV medications.

• Flush IV lines with 0.9% NaCl injection or D5W prior to and after infusion.

• If unable to administer IV diluted solution within 6 hours of preparation, immediately refrigerate (2–8 ºC) the infusion solution after dilution and complete the infusion within 24 hours; do not freeze.

• Oral capsules: Swallow oral capsules whole; do not chew, crush, dissolve, or open the capsule. Capsules may be taken with or without food.

• Switching between IV and oral formulations is acceptable as bioequivalence has been demonstrated; loading dose is not required when switching between formulations.

• Advise female patients of reproductive potential to use effective contraception during treatment and for 28 days after the final dose.

Monitoring Parameters

• Hypersensitivity reactions with initial doses.

• Liver function tests (e.g. measurement of serum levels of AST, ALT, ALP, and total bilirubin), at baseline and periodically during therapy.

• Infusion-related reactions (e.g. hypotension, dyspnea, chills, dizziness, paresthesias, and hypoesthesia) during IV infusion