Rezafungin

{{DrugProjectFormSinglePage |authorTag=HAFIZA AMNA QADEER, MD |OTC=Yes |genericName=REZAFUNGIN |aOrAn=an |drugClass=ANTIFUNGAL ECHINOCANDIN |indicationType=treatment |indication=Patients with invasive candidiasis and candidemia who are at least 18 years old and have few or no other options for treatment. |adverseReactions=Diarrhea, vomiting, nausea, abdominal pain, constipation, hypokalemia, hypomagnesemia, hypophosphatemia, pyrexia and anemia. |fdaLIADAdult=The recommended dosage of rezafungin is 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 rezafungin has not been established beyond 4 weekly doses. Rezafungin is used for intravenous infusion only. Administer rezafungin by intravenous infusion over approximately one hour (~250 mL/h). If infusion-related reactions occur, the infusion may be slowed, or paused and restarted at a lower rate. |contraindications=Rezafungin is contraindicated in patients with known hypersensitivity to rezafungin or other echinocandins. |warnings=* Infusion related reactions.

• Photosensitivity.
• Hepatic Adverse Reactions.

|clinicalTrials=The following adverse reaction can occur after administration of rezafungin:

GASTROINTESTINAL

Diarrhea, Nausea, Vomiting, Dysphagia, Gastrointestinal hemorrhage, abnormal liver tests (including hypertransaminasemia and increased gamma-glutamyltransferase), abdominal pain and constipation.

METABOLISM AND NUTRITION DISORDER

Anemia, Disseminated Intravascular Coagulation.

NERVOUS SYSTEM

Tremor, insomnia, headache, dizziness, peripheral neuropathy (includes neuropathy peripheral, polyneuropathy, and peroneal nerve palsy).

INTEGUMENTARY SYSTEM

Photosensitivity and erythema.

CARDIOVASCULAR SYSTEM

Fluid overload. |postmarketing=The following adverse reaction can occur after administration of rezafungin:

GASTROINTESTINAL

Diarrhea, Nausea, Vomiting, Dysphagia, Gastrointestinal hemorrhage, abnormal liver tests (including hypertransaminasemia and increased gamma-glutamyltransferase), abdominal pain and constipation.

METABOLISM AND NUTRITION DISORDER

Anemia, Disseminated Intravascular Coagulation.

NERVOUS SYSTEM

Tremor, insomnia, headache, dizziness, peripheral neuropathy (includes neuropathy peripheral, polyneuropathy, and peroneal nerve palsy).

INTEGUMENTARY SYSTEM

Photosensitivity and erythema.

CARDIOVASCULAR SYSTEM

Fluid overload. |drugInteractions=Rezafungin is not a substrate of CYP enzymes or drug transporter systems. Rezafungin is not an inhibitor or inducer of common drug metabolizing CYP enzymes or transporter systems. |useInPregnancyFDA=There are no data on the use of rezafungin during pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. |useInNursing=There are no data on the presence of rezafungin or its metabolite in human milk, the effects on the breastfed infant, or the effects on milk production. |useInPed=The safety and effectiveness of rezafungin have not been established in pediatric patients. |useInGeri=Clinical studies of Rezafungin did not include sufficient numbers of older adult patients to determine if patients 65 years and older respond differently than younger adult patients. |useInGender=Clinical studies of rezafungin did not include sufficient numbers of older adult patients to determine if patients 65 years and older respond differently than younger adult patients. |useInRenalImpair=No clinically relevant effect on the pharmacokinetics 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. |useInHepaticImpair=No clinically relevant effects on the pharmacokinetics of rezafungin were observed with hepatic impairment (Child Pugh Class B or C). |useInReproPotential=The effect of rezafungin on human fertility is unknown. |administration=Administer Rezafungin by intravenous infusion over approximately one hour (~250 mL/h). If infusion-related reactions occur, the infusion may be slowed, or paused and restarted at a lower rate. |overdose=No cases of overdose were reported during the clinical studies. Rezafungin is highly protein bound and not anticipated to be dialyzable. |mechAction=Rezafungin is a semi-synthetic echinocandin. Rezafungin inhibits the 1,3-β-D-glucan synthase enzyme complex, which is present in fungal cell walls but not in mammalian cells. This results in inhibition of the formation of 1,3-β-D-glucan, an essential component of the fungal cell wall of many fungi, including Candida species (spp.). Inhibition of 1,3-β-D-glucan synthesis results in concentration-dependent in vitro fungicidal activity against Candida spp., however, the clinical significance of this activity is unknown. |structure=REZZAYO (rezafungin for injection), for intravenous use is a sterile solid (cake or powder) that contains rezafungin acetate. Rezafungin acetate is a semisynthetic lipopeptide synthesized from a fermentation product of Aspergillus nidulans. REZZAYO is an echinocandin, a class of antifungal drugs that inhibits the synthesis of 1,3-β-D-glucan, an essential component of fungal cell walls. REZZAYO contains 210 mg of rezafungin acetate, equivalent to 200 mg of rezafungin. REZZAYO also contains 47 mg histidine, 500 mg mannitol, 450 mg polysorbate 80, and hydrochloric acid and/or sodium hydroxide for pH adjustment. Rezafungin acetate is a hygroscopic, white to off-white powder. It is freely soluble in water, soluble in methanol, and sparingly soluble in ethanol. Rezafungin acetate is chemically designated as Echinocandin B, 1-[(4R,5R)-4-hydroxy-N2-[[4"- (pentyloxy)[1,1':4',1"-terphenyl]-4-yl]carbonyl]-5-[2-(trimethylammonio)ethoxy]-L-ornithine]-4-[(4S)-4- hydroxy-4-(4-hydroxyphenyl)-L-allothreonine]-, acetate (1:1). The empirical formula of Rezafungin acetate is C63H85N8O17 • C2H3O2, and the formula weight is 1285.46 g/mol. |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. Rezafungin does not prolong the QTc interval to any clinically relevant extent at a dose 3.5 times the maximum approved recommended loading dose. |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. |nonClinToxic==CARCINOGENESIS= Carcinogenicity studies with rezafungin have not been conducted.

MUTAGENESIS

Rezafungin was negative in a standard battery of assays, including an in vitro bacterial reverse mutation assay, an in vitro mammalian clastogenicity assay, and an in vivo rat bone marrow micronucleus assay.

IMPAIRMENT OF FERTILITY

Rezafungin did not affect mating or fertility in male and female rats following IV administration once every 3 days at doses up to 45 mg/kg (6 times the clinical exposure, based on AUC determined in a separate rat study). Decreased sperm motility was noted at ≥30 mg/kg and most males at 45 mg/kg showed mild/moderate hypospermia and had no detectable motile sperm. At rezafungin doses ≥30 mg/kg there was an increased incidence of sperm with abnormal morphology as well as mild to moderate degeneration of the seminiferous tubules. In a 3-month study of every 3 day IV rezafungin in rats, males dosed at 45 mg/kg showed minimal tubular degeneration/atrophy in the testes and cellular debris in the epididymides at the end of 3 months. The incidence of this finding reduced by the end of a 4-week reversibility period. In contrast, sperm concentration, production rate, morphology and motility were unaffected in adult monkeys dosed weekly with rezafungin, up to 30 mg/kg (about 6 times the clinical dose based on AUC comparisons) for 11 or 22 weeks or after a 52-week recovery period. |clinicalStudies=The safety and efficacy of REZZAYO in the treatment of patients with candidemia and/or invasive candidiasis (IC) were evaluated in a multicenter, randomized, double-blind study (Trial 1; NCT03667690). Patients were randomized in a 1:1 ratio to receive REZZAYO or caspofungin. Randomization was stratified based on diagnosis (candidemia only; IC) and by Acute Physiology and Chronic Health Evaluation II score (APACHE II)/absolute neutrophil count (ANC) at screening. Patients with septic arthritis in a prosthetic joint, osteomyelitis, endocarditis or myocarditis, meningitis, endophthalmitis, chorioretinitis, or any central nervous system infection, chronic disseminated candidiasis, or urinary tract candidiasis due to ascending Candida infection secondary to obstruction or surgical instrumentation of the urinary tract were excluded.

Patients in the REZZAYO arm were to receive a single 400 mg loading dose on Day 1 of Week 1, followed by 200 mg once weekly, for a total of two to four doses. Patients in the caspofungin arm were to receive a single 70 mg IV loading dose, followed by caspofungin 50 mg IV once daily treatment for a total of 2 to 4 weeks. After ≥3 days of IV therapy, patients in the caspofungin group could be switched to oral step-down therapy (fluconazole), if the patient met the criteria for cure and was preparing to be discharged.

One hundred and ninety-nine patients in the intent-to-treat (ITT) population were randomized. The age range was 19-91 years, the gender distribution was 62% male and 38% female, and the race distribution was 61% White, 5% Black, 29% Asian, and 5% other races or not reported. The median duration of therapy was 14 days in the two treatment arms.

The modified ITT (mITT) population included 187 patients with a culture positive for Candida species within 4 days before randomization and who received at least one dose of study drug. The most frequent species isolated at baseline was C. albicans (42%), followed by C. glabrata (26%), C. tropicalis (20%), and C. parapsilosis (13%). The majority (70%) of patients had a diagnosis of candidemia only. The majority (93%) of patients were not neutropenic (ANC ≥500) and 84% had APACHE II scores less than 20. Risk factors for candidemia were: receipt of broad-spectrum antibacterial drugs (71%), presence of a central venous catheter (60%), major surgery (35%), diabetes mellitus (29%), active malignancy (25%), and total parenteral nutrition (20%). Mechanically ventilated patients were 24% (17% and 30% in the REZZAYO and caspofungin group, respectively).

Efficacy was assessed by all-cause mortality at Day 30. The number and percentage of patients in each treatment group who were alive and deceased/unknown survival status at Day 30 was determined in the mITT population. 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. |howSupplied=Rezafungin is supplied as a single-dose vial containing 200 mg of Rezafungin. For the 400 mg dose, aseptically reconstitute two vials each with 9.5 mL of sterile Water for Injection, to provide a concentration of 20 mg/mL in each vial. For the 200 mg dose, aseptically reconstitute one vial with 9.5 mL of sterile Water for Injection, to provide a concentration of 20 mg/mL |storage=Store Rezafungin infusion solution between 5°C to 25°C (41°F to 77°F). Stability of the infusion solution has been demonstrated for 48 hours at 5°C to 25°C (41°F to 77°F). |brandNames=REZZAYO }}