Isavuconazole

Common name: Isavuconazole lyophilized powder for injection

Trade name: Cresemba

Full names: Isavuconazole lyophilized powder for injection, Cresemba, Isavuconazole, isavuconazonium sulfate

Indications:

(1) For the treatment of invasive aspergillosis in adults; (2) For the treatment of mucormycosis in adults who are not suitable for amphotericin B.

Dosage:

Dosage

Early targeted therapy (preemptive or diagnostic-driven therapy) may be started before specific diagnostic tests confirm the disease. However, once these results are obtained, antifungal treatment should be adjusted accordingly.

Loading dose

The recommended loading dose is one bottle (equivalent to 200 mg isavuconazole) reconstituted and diluted every 8 hours for the first 48 hours (a total of 6 doses).

Maintenance dose

The recommended maintenance dose is one vial reconstituted and diluted (equivalent to 200 mg isavuconazole) once daily starting 12 to 24 hours after the last loading dose.

Duration of treatment should be determined by clinical response.

For long-term treatment beyond 6 months, the benefit-risk balance should be carefully considered.

Switch to oral isavuconazole

CRESEMBA is also available as a hard capsule containing 100 mg of isavuconazole.

Based on the high oral bioavailability (98%, see Section 5.2), switching between intravenous and oral administration is appropriate when clinically indicated.

Geriatric

No dose adjustment is required in elderly patients; however, clinical experience with elderly patients is limited.

Renal Impairment

No dose adjustment is required in patients with renal insufficiency, including patients with end-stage renal disease.

Hepatic Impairment

No dose adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh Class A and B).

Isavuconazole has not been studied in patients with severe hepatic impairment (Child-Pugh class C). Use in these patients is not recommended unless the potential benefits are considered to outweigh the risks.

Pediatric Population

The safety and effectiveness of CRESEMBA in children under 18 years of age have not been established. No data available.

Administration

Intravenous use.

Precautions before handling or using the drug

CRESEMBA must be reconstituted and then further diluted to a concentration corresponding to approximately 0.8 mg/mL isavuconazole by intravenous infusion at least 1 hour before administration to reduce the risk of infusion-related reactions. The infusion must be administered through an infusion set with an in-line filter with a microporous membrane made of polyethersulfone (PES) with a pore size of 0.2 μm to 1.2 μm. CRESEMBA must be given as an intravenous infusion only.

Detailed instructions for reconstitution and dilution of CRESEMBA prior to administration.

Strength:

200mg 1vial (injection)

Adverse Reactions:

Most frequent adverse reactions: nausea, vomiting, diarrhea, headache, elevated liver chemistry tests, hypokalemia, constipation, dyspnea, cough, peripheral edema, and back pain.

Contraindications:

Hypersensitivity to the active substance or any of the listed excipients.

Coadministered with ketoconazole.

Coadminister with high-dose ritonavir (>200 mg every 12 hours).

Coadminister with strong CYP3A4/5 inducers such as rifampicin, rifabutin, carbamazepine, long-acting barbiturates (e.g., phenobarbital), phenytoin, and St. John's wort or with moderate CYP3A4/5 inducers such as efavirenz, nafcillin, and etravirine.

Patients with familial short QT syndrome.

Precautions:

Hepatic adverse drug reactions: Serious liver reactions have been reported. Evaluate liver-related laboratory tests at the beginning and during the course of CRESEMBA treatment.

Infusion-related reactions have been reported during intravenous administration of CRESEMBA. If these reactions occur, terminate the infusion.

Hypersensitivity Reactions: Severe hypersensitivity and severe skin reactions, such as anaphylaxis or Stevens Johnson syndrome, have been reported during treatment with other azole antifungals. Discontinue CRESEMBA for exfoliative skin reactions.

Embryo-fetal toxicity: Do not give to pregnant women unless the maternal benefit outweighs the risk to the fetus. Inform pregnant patients of the hazards.

Drug Interactions: Review patients' concomitant medications. Several drugs may significantly alter isavuconazole concentrations. Isavuconazole may alter the concentrations of several drugs.

Drug particles: Insoluble particles may form after reconstitution of intravenous preparations. Administer CRESEMBA through an in-line filter.

Storage:

Store in refrigerator (2°C to 8°C).

Mechanism of action:

Isavuconazole is the active moiety formed after oral or intravenous injection of isavuconazole sulfate.

Isavuconazole exhibits fungicidal effects by blocking the synthesis of ergosterol, a key component of fungal cell membranes, by inhibiting the cytochrome P-450-dependent enzyme lanosterol 14-alpha-demethylase, which is responsible for converting lanosterol to ergosterol. This results in the accumulation of methylated sterol precursors and depletion of ergosterol within the cell membrane, thereby weakening the structure and function of the fungal cell membrane.

Safety and Efficacy:

Intratracheal infection of neutropenic mice with Rhizopus delemar or Mucor circinelloides. The researchers treated mice with isavuconazole, L-AMB in combination or alone for 8 hours after infection and continued until day 4, and placebo mice received vehicle control. Tissue fungal burden in mice surviving to day 21 and day 4 served as primary and secondary endpoints, respectively.

For infected mice, compared with L-AMB and placebo, isavuconazole and L-AMB prolonged the median survival time of mice and increased the survival rate of mice. The overall survival rate of mice using the two drugs alone was 50%, while the placebo was only 5%, while the overall survival rate of mice treated with the two drugs in combination was 80%! And compared with the placebo, the fungal burden in any organ was reduced by 2.0-3.5% when the two drugs were used in combination. log, while a single drug reduced 1.0-2.0 log.

The conclusion is that isavuconazole combined with L-AMB is more effective in treating mucormycosis than monotherapy. From the experimental data obtained in this study, it can be seen that isavuconazole combined with L-AMB therapy may become the best new therapy for the treatment of mucormycosis.