CRESEMBA® (isavuconazonium sulfate) is indicated for the treatment of invasive aspergillosis and invasive mucormycosis in adults. Usage
Pharmacokinetic profile of isavuconazole
CRESEMBA (isavuconazonium sulfate) is a prodrug containing the active moiety isavuconazole, an azole antifungal drug.1
Dose-proportional pharmacokinetics following administration of CRESEMBA1,2
- No significant association between area under the curve (AUC) or drug concentration and efficacy in patients treated for invasive aspergillosis in a controlled trial1
|Steady state pharmacokinetic parameters of isavuconazole following administration of CRESEMBA capsules1|
|Parameter||CRESEMBA 2 capsules*
|CRESEMBA 6 capsules*
*Each capsule contains the equivalent of 100 mg of isavuconazole.
Cmax=maximum plasma concentration; Tmax=time to reach Cmax; SD=standard deviation; CV=coefficient of variation.
- Dose-proportional increases in exposure following oral (PO) administration of CRESEMBA doses up to the equivalent 600 mg/day of isavuconazole (6 capsules)1
- Mean plasma half-life of isavuconazole was 130 hours based on a population pharmacokinetics analysis of healthy subjects and patients in clinical trials1
- No differences noted in clearance between healthy subjects and clinical trial patients based on population pharmacokinetic modeling (mean AUC [mg•h/L] 92.3 and 97.9, respectively; between-subject variability of <60%)†2
†Based on a 2-compartment model developed using data from Phase 1 subjects and Phase 3 trial patients administered single and multiple, PO and intravenous (IV) doses of CRESEMBA.2
- 98% absolute bioavailability following PO administration
- CRESEMBA can be taken with or without food
- Reaches Cmax 2–3 hours after single and multiple PO dosing
- Extensively distributed with a mean steady state volume of distribution of 450 L
- Highly protein bound (>99%) predominantly to albumin
- Isavuconazonium sulfate is rapidly hydrolyzed in blood to isavuconazole by esterases
- Isavuconazole is a substrate of cytochrome P450 enzymes 3A4 and 3A5
- In vivo studies indicate that CYP3A4, CYP3A5, and subsequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole
Mean total radioactive dose of CRESEMBA® (isavuconazonium sulfate)‡:
- 46.1% was recovered in the feces
- 45.5% was recovered in the urine
- Renal excretion of isavuconazole was <1% of the dose administered
‡Following PO administration in healthy volunteers.
No dose adjustments required in specific populations based on1:
Mild, moderate, or severe renal impairment, including end-stage renal disease
- Of the 403 patients who received CRESEMBA in the Phase 3 trials, 79 (20%) patients had an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2
- CRESEMBA is not removed by hemodialysis
Mild to moderate hepatic impairment
- CRESEMBA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Monitoring for CRESEMBA-related adverse reactions is recommended when treating these patients
- Age or gender
IMPORTANT SAFETY INFORMATION AND USE OF CRESEMBA
- CRESEMBA is contraindicated in persons with known hypersensitivity to isavuconazole
- Coadministration of strong CYP3A4 inhibitors, such as ketoconazole or high-dose ritonavir (400 mg every 12 hours), with CRESEMBA is contraindicated because strong CYP3A4 inhibitors can significantly increase the plasma concentration of isavuconazole
- Coadministration of strong CYP3A4 inducers, such as rifampin, carbamazepine, St. John's wort, or long acting barbiturates with CRESEMBA is contraindicated because strong CYP3A4 inducers can significantly decrease the plasma concentration of isavuconazole
- CRESEMBA shortened the QTc interval in a concentration-related manner. CRESEMBA is contraindicated in patients with familial short QT syndrome
WARNINGS AND PRECAUTIONS
Hepatic Adverse Drug Reactions (e.g., elevations in ALT, AST, alkaline phosphatase, total bilirubin) have been reported in clinical trials and were generally reversible and did not require discontinuation of CRESEMBA. Cases of severe hepatic adverse drug reactions including hepatitis, cholestasis or hepatic failure including death have been reported in patients with serious underlying medical conditions (e.g., hematologic malignancy) during treatment with azole antifungal agents, including CRESEMBA. Evaluate liver tests at the start and during therapy. Monitor patients who develop liver abnormalities during CRESEMBA therapy for severe hepatic injury. Discontinue if clinical signs and symptoms consistent with liver disease develop that may be attributable to CRESEMBA.
Infusion-Related Reactions including hypotension, dyspnea, chills, dizziness, paresthesia, and hypoesthesia were reported during intravenous administration of CRESEMBA. Discontinue the infusion if these reactions occur.
Serious Hypersensitivity and Severe Skin Reactions, such as anaphylaxis or Stevens Johnson syndrome, have been reported during treatment with other azole antifungal agents. Discontinue CRESEMBA if a patient develops a severe cutaneous adverse reaction. Caution should be used when prescribing CRESEMBA to patients with hypersensitivity to other azoles.
Embryo-Fetal Toxicity: During pregnancy, CRESEMBA may cause fetal harm when administered, and CRESEMBA should only be used if the potential benefit to the patient outweighs the risk to the fetus. Women who become pregnant while receiving CRESEMBA are encouraged to contact their physician.
Drug Interactions: Coadministration of CRESEMBA with strong CYP3A4 inhibitors such as ketoconazole or high-dose ritonavir and strong CYP3A4 inducers such as rifampin, carbamazepine, St. John's Wort, or long-acting barbiturates is contraindicated.
Drug Particulates: Following dilution, CRESEMBA intravenous formulation may form precipitate from the insoluble isavuconazole. Administer CRESEMBA through an in-line filter.
The most frequently reported adverse reactions among CRESEMBA-treated patients were nausea (26%), vomiting (25%), diarrhea (22%), headache (17%), elevated liver chemistry tests (16%), hypokalemia (14%), constipation (13%), dyspnea (12%), cough (12%), peripheral edema (11%), and back pain (10%).
The adverse reactions which most often led to permanent discontinuation of CRESEMBA therapy during the clinical trials were: confusional state (0.7%), acute renal failure (0.7%), increased blood bilirubin (0.5%), convulsion (0.5%), dyspnea (0.5%), epilepsy (0.5%), respiratory failure (0.5%), and vomiting (0.5%).
INDICATIONS AND USAGE
CRESEMBA is an azole antifungal indicated for patients 18 years of age and older for the treatment of invasive aspergillosis and invasive mucormycosis.
Specimens for fungal culture and other relevant laboratory studies (including histopathology) to isolate and identify causative organism(s) should be obtained prior to initiating antifungal therapy. Therapy may be instituted before the results of the cultures and other laboratory studies are known. However, once these results become available, antifungal therapy should be adjusted accordingly.
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