Rezafungin

1 INDICATIONS AND USAGE REZZAYO is an echinocandin antifungal indicated in patients 18 years of age or older who have limited or no alternative options for the treatment of candidemia and invasive candidiasis. Approval of this indication is based on limited clinical safety and efficacy data for REZZAYO. ( 1 , 12.4 , 14 ) Limitations of Use REZZAYO has not been studied in patients with endocarditis, osteomyelitis, and meningitis due to Candida. ( 1 ) 1.1 Indication REZZAYO is indicated in patients 18 years of age or older who have limited or no alternative options for the treatment of candidemia and invasive candidiasis [see Microbiology ( 12.4 )] . Approval of this indication is based on limited clinical safety and efficacy data for REZZAYO [see Clinical Studies ( 14 )] . Limitations of Use REZZAYO has not been studied in patients with endocarditis, osteomyelitis, and meningitis due to Candida . 1.2 Usage Specimens for culture and other laboratory data (e.g., histopathology, non-culture diagnostics) should be obtained prior to initiating antifungal therapy. Therapy may be initiated before the results of the cultures and other laboratory tests are known. However, once these results become available, antifungal therapy should be adjusted accordingly.

2 DOSAGE AND ADMINISTRATION Administer the recommended dosage of REZZAYO 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. ( 2.1 ) See full prescribing information for reconstitution, dilution, and administration instructions. ( 2.2 , 2.3 , 2.4 ) 2.1 Recommended Dosage Administer the recommended dosage of REZZAYO 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 [see Adverse Reactions ( 6.1 )] . REZZAYO is for intravenous infusion only [see Dosage and Administration ( 2.4 )] . 2.2 Missed Doses If a scheduled dose is missed (not taken on the assigned day), administer the missed dose as soon as possible. If the missed dose is administered within 3 days of the assigned day, the next weekly dose may be given on schedule. If the missed dose is administered more than 3 days after the assigned day, revise the dosing schedule to ensure there are at least 4 days before the next dose. If restarting after at least 2 weeks of missed dosing, the dosing should be started again at the 400 mg loading dose. 2.3 Preparation and Administration of REZZAYO Reconstitution REZZAYO 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. Swirl gently to dissolve the white to pale yellow cake or powder. Avoid shaking to minimize foaming. The solution should be clear to pale yellow after dissolution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if the reconstituted solution is cloudy or has precipitated. The reconstituted solution is not for direct injection and must be diluted before intravenous infusion. Storage of the Reconstituted Solution REZZAYO reconstituted solution can be stored between 5°C to 25°C (41°F to 77°F). Stability of the reconstituted solution has been demonstrated for 24 hours when stored at 5°C to 25°C (41°F to 77°F). Preparation of Intravenous Infusion Solution See Table 1 for the dilution requirements for infusion solution. First, aseptically withdraw and discard the appropriate volume of diluent from the intravenous bag containing 250 mL of 0.9% Sodium Chloride Injection, 0.45% Sodium Chloride Injection, or 5% Dextrose Injection. Next, aseptically transfer the indicated volume of reconstituted solution (10 mL per vial) into the intravenous bag. REZZAYO vials are single-dose vials. Discard any unused portion. Table 1: Dilution Requirements for REZZAYO Prior to Administration Dose Number of 200 mg Vials Required Total Reconstituted Volume Required Infusion Diluent Volume Discarded Infusion Diluent Volume Used Total Infusion Volume 400 mg 2 20 mL 20 mL 230 mL 250 mL Infusion solution concentration for the 400 mg dose = 1.6 mg/mL 200 mg 1 10 mL 10 mL 240 mL 250 mL Infusion solution concentration for the 200 mg dose = 0.8 mg/mL Storage of the Intravenous Infusion Solution Store REZZAYO 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). The infusion solution must not be frozen. 2.4 Administration of Intravenous Infusion Solution Administer REZZAYO 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 [see Warnings and Precautions ( 5.1 )] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions, including Anaphylaxis [see Warnings and Precautions ( 5.1 )] Infusion-related Reactions [see Warnings and Precautions ( 5.2 )] Hepatic Adverse Reactions [see Warnings and Precautions ( 5.4 )] Most common adverse reactions (incidence ≥ 5%) are hypokalemia, pyrexia, diarrhea, anemia, vomiting, nausea, hypomagnesemia, abdominal pain, constipation, and hypophosphatemia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Melinta Therapeutics at 1-844-633-6568 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of REZZAYO cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of REZZAYO was assessed in 76 subjects in phase 1 studies and 232 patients with candidemia and invasive candidiasis in Trials 1 and 2, who received a 400 mg loading dose followed by a 200 mg dose once weekly or higher (please note that after the loading dose of 400 mg, weekly doses higher than 200 mg are not approved). A total of 151 patients received an initial 400 mg loading dose followed by a 200 mg dose once weekly thereafter (400 mg/200 mg dose); the maximum duration of dosing was 4 weekly doses (including the loading dose). In the pooled Trial 1 and 2 safety database of REZZAYO patients treated with the 400 mg/200 mg dose, the age range was 19-91 years, the gender distribution was 64.9% male and 35.1% females, and the race distribution was 66.2% White, 7.9% Black, 17.9% Asian, 2.7% other, and 5.3% not reported. Adverse Reactions Leading to Discontinuation in Patients with Candidemia and Invasive Candidiasis The number of patients with an adverse reaction leading to discontinuation of study medication was 9.3% in the REZZAYO arm and 9.0% in the caspofungin arm. In Trial 2, patients with a history (or presenting with significant symptoms) of severe ataxia, tremor, or neuropathy or a diagnosis of multiple sclerosis or a movement disorder (including Parkinson's Disease or Huntington's Disease) or currently taking a known neurotoxic medication were excluded from the trial. Most Common Adverse Reactions in Patients with Candidemia and Invasive Candidiasis Selected adverse reactions occurring in 5% or more of the patients, who received a 400 mg loading dose followed by a 200 mg dose of REZZAYO once weekly are shown in Table 2 . Table 2: Adverse Reactions Reported in ≥5% of Adult Patients Receiving REZZAYO Therapy for Candidemia/Invasive Candidiasis Adverse Reaction REZZAYO N = 151 n (%) Caspofungin N = 166 n (%) Gastrointestinal disorders Diarrhea 17 (11%) 17 (10%) Vomiting 14 (9%) 7 (4%) Nausea 13 (9%) 8 (5%) Abdominal pain 11 (7%) 9 (5%) Constipation 8 (5%) 8 (5%) Metabolism and nutrition disorders Hypokalemia 22 (15%) 17 (10%) Hypomagnesemia 12 (8%) 5 (3%) Hypophosphatemia 8 (5%) 5 (3%) General disorders Pyrexia 18 (12%) 11 (7%) Blood and lymphatic system disorders Anemia 15 (10%) 13 (8%) Less Common Adverse Reactions in Patients with Candidemia and Invasive Candidiasis The following selected adverse reactions occurred in <5% of patients receiving REZZAYO: infusion-related reactions, tremor, disseminated intravascular coagulation, dysphagia, gastrointestinal hemorrhage, fluid overload, insomnia, erythema, headache, dizziness, acute kidney injury, abnormal liver tests (including hypertransaminasemia and increased gamma-glutamyltransferase), peripheral neuropathy (includes neuropathy peripheral, polyneuropathy, and peroneal nerve palsy). Tremors Tremors were reported in 4/151 (2.6%) of REZZAYO-treated patients and none of the caspofungin-treated patients in Trials 1 and 2. All tremors developed in the second or third week after initiation of REZZAYO treatment and resolved within a month of onset. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of REZZAYO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders : drug hypersensitivity, anaphylactic reaction

12.3 Pharmacokinetics Following single and multiple dosing, the C max 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. Rezafungin population PK model derived pharmacokinetics (in patients with candidemia and invasive candidiasis (IC)) following administration of REZZAYO 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 Pharmacokinetic (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 Value Mean ± SD Exposure Day 1 Day 15 C max (mcg/mL) Time to C max is 1hr post-start of infusion (i.e., end of infusion) 19.2 ± 5.9 11.8 ± 3.5 AUC 0-168 (mcg∙h/mL) 827 ± 252 667 ± 224 C min (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±28L 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 Excretion Excretion studied in healthy subjects 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 Specific Populations No clinically relevant effects on the pharmacokinetics 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 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. Drug Interaction Studies Clinical Studies Drug-drug interaction studies' findings in healthy subjects show that at the recommended rezafungin dosing regimen, no clinically significant effect is expected of rezafungin treatment on the pharmacokinetics of substrates of cytochrome P450 (CYP) enzymes and/or drug transporters (repaglinide [CYP2C8], cyclosporine [CYP3A and P-gp], tacrolimus [CYP3A and P-gp], caffeine [CYP1A2], midazolam [CYP3A]), metformin [OCT-1 and OCT-2 and MATE-1 and MATE-2], pitavastatin [OATP], rosuvastatin [BCRP and OATP], digoxin [P-gp]). These studies also show no clinically significant effect expected of rezafungin treatment on the pharmacokinetics of other drugs likely to be co-administered (ibrutinib, venetoclax, efavirenz, or mycophenolate mofetil). In Vitro Studies 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.