Author: [AUTHOR] Published on 5/12/2023 6:00:00 AM
FDA Approves REZZAYO (Rezafungin) for Adult Patients with Candidemia and Invasive Candidiasis Who Have Limited or No Alternative Treatment Options
On March 22, 2023, the US Food and Drug Administration (FDA) approved REZZAYO (rezafungin) for patients 18 years of age or older who have limited or no alternative options for the treatment of candidemia and invasive candidiasis (IC). Approval of this indication is based on limited clinical safety and efficacy data for REZZAYO. REZZAYO has not been studied in patients with endocarditis, osteomyelitis, and meningitis due to Candida.
The recommended dosage of REZZAYO is administered once weekly by intravenous (IV) infusion, with an initial 400 mg loading dose, followed by a 200 mg dose once weekly thereafter. The safety of REZZAYO has not been established beyond 4 weekly doses.
REZZAYO is contraindicated in patients with known hypersensitivity to rezafungin or other echinocandins.
Additional information regarding dosage and administration as well as warnings and precautions about infusion-related reactions, photosensitivity, and hepatic adverse reactions can be found in the full prescribing information linked below.
Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD)
MOA: Rezafungin is an echinocandin antifungal agent.
General PK: Following single and multiple dosing, the Cmax and AUC of rezafungin increase in a dose-proportional manner over a dose range of 50 mg (0.125 times the approved maximum recommended loading dose) to 400 mg.
The PK of rezafungin in patients with candidemia and IC following administration of REZZAYO, derived from population-PK modeling, are provided in Table 3 and presented as mean ± standard deviation (SD). The mean rezafungin AUC
0-168h decreased approximately 30% and C
max decreased approximately 19% in patients with candidemia and IC compared to healthy participants.
Table 3: Population PK Parameters of Rezafungin in Patients with Candidemia or IC Following REZZAYO (initial 400 mg loading dose, followed by a 200 mg dose once weekly).
| Parameter |
Valuea |
| Exposure |
Day 1 |
Day 15 |
| Cmax (mcg/mL)b |
19.2 ± 5.9 |
11.8 ± 3.5 |
| AUC0-168 (mcg∙h/mL) |
827 ± 252 |
667 ± 224 |
| Cmin (mcg/mL) |
2.4 ± 0.9 |
2.2 ± 0.9 |
| Distribution |
| % Bound to human plasma proteins |
Mean estimates varied from 87.5% to 93.6% in patients
Mean estimates varied from 95.6% to >98.6% in healthy adults
|
| Volume of distribution (V) |
67 ± 28 L |
|
| Elimination |
| Clearance (CL) |
0.35 ± 0.13 L/hr |
|
| terminal half-life (t1/2) |
152 ± 29 hours |
|
| Metabolism |
| Metabolic pathways |
Hepatic metabolism of rezafungin has not been observed. It is unlikely that rezafungin is a clinically relevant substrate of CYP450 enzymes |
|
| Excretionc |
| Major route of elimination |
Fecal excretion |
|
| % feces |
74.3% of recovered radioactivity, primarily as rezafungin |
|
| % urine |
25.7% of recovered radioactivity, primarily as inactive metabolites |
|
C
max= maximum plasma concentration; C
min= trough plasma concentration; AUC
0–168h= area under the plasma concentration-time curve from time zero to 168 hours post dose
a Mean ± SD
b Time to C
max is 1hr post-start of infusion (i.e., end of infusion)
c Excretion studied in healthy subjects
PD: Rezafungin exposures achieved with the recommended dosage regimen appear to be on the plateau of the observed flat exposure-efficacy response curve in clinical studies.
Use in Specific Populations
No clinically relevant effects on the PK of rezafungin were observed based on age (range: 20 to 89 years), sex (60.6% male), race (~10% Asian, 10% Black, 77% White), weight (range: 34 to 154.5 kg), or hepatic impairment (Child Pugh Class B or C). No clinically relevant effect on the PK of rezafungin were observed based on renal impairment (creatinine clearance: 9.3 mL/min to above 120 mL/min) and no effect is expected in patients undergoing hemodialysis.
Efficacy and Safety
Efficacy of REZZAYO in the treatment of patients with candidemia and/or IC was demonstrated in a multicenter, randomized, double-blind study. Efficacy was assessed by all-cause mortality at Day 30. Additional efficacy outcomes were global cure (mycological eradication/presumed eradication, clinical cure, and radiological cure [for patients with documented IC by radiologic or other imaging findings at baseline]), mycological eradication/presumed eradication, and investigator’s assessment of clinical cure. Additional information regarding the efficacy study can be found in the full prescribing information linked below.
Most common adverse reactions (incidence ≥ 5%) are hypokalemia, pyrexia, diarrhea, anemia, vomiting, nausea, hypomagnesemia, abdominal pain, constipation, and hypophosphatemia.
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REZZAYO full prescribing information page to learn more about REZZAYO.
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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.