Rezafungin

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-[(4 R ,5 R )-4-hydroxy- N 2 -[[4"- (pentyloxy)[1,1':4',1"-terphenyl]-4-yl]carbonyl]-5-[2-(trimethylammonio)ethoxy]-L-ornithine]-4-[(4 S )-4- hydroxy-4-(4-hydroxyphenyl)-L-allothreonine]-, acetate (1:1). The empirical formula of rezafungin acetate is C 63 H 85 N 8 O 17 • C 2 H 3 O 2 , and the formula weight is 1285.46 g/mol. The chemical structure of rezafungin acetate is: chemicalstructure

REZZAYO is an echinocandin antifungal indicated in adults and pediatric patients 12 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 Treatment of Candidemia and Invasive Candidiasis REZZAYO is indicated in adults and pediatric patients 12 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.

16.1 How Supplied REZZAYO (rezafungin for injection) is supplied as sterile white to pale yellow solid (cake or powder) in a single-dose 20 mL Type I glass vial with a stopper, an aluminum seal, and blue polypropylene flip-off cap. The vial stopper is not made with natural rubber latex. REZZAYO is available in the following packaging configuration: One single-dose vial of REZZAYO 200 mg (NDC 70842-240-01) 16.2 Storage and Handling REZZAYO Vials REZZAYO vials should be stored at 20°C to 25°C (68°F to 77°F). Brief exposure to 15°C to 30°C (59°F to 86°F) permitted [see USP Controlled Room Temperature]. Reconstituted Solution REZZAYO reconstituted solution can be stored between 5°C (41°F) and 25°C (77°F) for up to 24 hours [see Dosage and Administration ( 2.3 )] . IV Infusion Solution REZZAYO infusion solution can be stored between 5°C (41°F) and 25°C (77°F) for up to 48 hours. Do not freeze [see Dosage and Administration ( 2.3 )] . 16.1 How Supplied REZZAYO (rezafungin for injection) is supplied as sterile white to pale yellow solid (cake or powder) in a single-dose 20 mL Type I glass vial with a stopper, an aluminum seal, and blue polypropylene flip-off cap. The vial stopper is not made with natural rubber latex. REZZAYO is available in the following packaging configuration: One single-dose vial of REZZAYO 200 mg (NDC 70842-240-01)

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 for Adults and Pediatric Patients 12 Years of Age or Older 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 )] .

REZZAYO is contraindicated in patients with known hypersensitivity to rezafungin or other echinocandins. Known hypersensitivity to rezafungin or other echinocandins. ( 4 )

Hypersensitivity Reactions, including Anaphylaxis: Cases of serious hypersensitivity reactions, including anaphylaxis, have been reported in patients receiving REZZAYO. If these reactions occur, discontinue REZZAYO and administer appropriate treatment ( 5.1 ). Infusion-related Reactions: REZZAYO may cause infusion-related reactions, including flushing, sensation of warmth, urticaria, nausea, or chest tightness. If these reactions occur, slow or pause the infusion. ( 5.2 ) Photosensitivity: REZZAYO may cause photosensitivity. Advise patients to use protection from sun exposure and other sources of UV radiation. ( 5.3 ) Hepatic Adverse Reactions: Abnormalities in liver tests have been seen in clinical trial patients treated with REZZAYO. Monitor patients who develop abnormal liver tests and evaluate patients for their risk/benefit of continuing REZZAYO therapy. ( 5.4 ) 5.1 Hypersensitivity Reactions, including Anaphylaxis Cases of serious hypersensitivity reactions, including anaphylaxis, have been reported in patients receiving REZZAYO. If these reactions occur, discontinue REZZAYO and administer appropriate treatment [see Adverse Reactions ( 6.2 )] . 5.2 Infusion-Related Reactions Infusion-related reactions, including flushing, sensation of warmth, urticaria, nausea, and chest tightness have been observed in clinical trials with REZZAYO [see Adverse Reactions ( 6.1 )] . If these reactions occur, slow or pause the infusion and restart at a lower rate [see Dosage and Administration ( 2.4 )] . 5.3 Photosensitivity REZZAYO may cause photosensitivity. Patients should be advised to use protection from sun exposure and other sources of UV radiation during REZZAYO treatment. 5.4 Hepatic Adverse Reactions Abnormalities in liver tests have been seen in clinical trial patients treated with REZZAYO [see Adverse Reactions ( 6.1 )] . In some patients with serious underlying medical conditions who were receiving multiple concomitant medications along with REZZAYO, clinically significant hepatic abnormalities have occurred. Monitor patients who develop abnormal liver tests during REZZAYO therapy and evaluate patients for their risk/benefit of continuing REZZAYO therapy.

Serious Allergic Reactions Advise patients that serious allergic reactions could occur with REZZAYO and that serious reactions require immediate treatment [see Warnings and Precautions ( 5.1 )]. Photosensitivity Advise patients to use protection against sun exposure and other sources of UV radiation during treatment because REZZAYO may cause photosensitivity [see Warnings and Precautions ( 5.2 )] . Distributed by: Melinta Therapeutics LLC Parsippany, NJ 07054 USA Manufactured by: Patheon Italia S.p.A., a Thermo Fisher Scientific company Viale Gian Battista Stucchi 110 20900 Monza (MB) Italy MEL150-R0002

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.

Risk Summary There are no data on the use of REZZAYO during pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. No adverse embryofetal outcomes were observed when rezafungin was dosed intravenously to pregnant rats or rabbits during the period of organogenesis up to approximately 5 or 3 times the clinical exposure based on AUC comparison (see Data ) . In a pre- and post- natal study, there were no adverse effects on offspring growth, maturation, or measures of neurobehavioral or reproductive function in rats at doses up to about 5 times the recommended human dose based on AUC comparisons. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an embryofetal development study, intravenous rezafungin was administered at doses up to 45 mg/kg, once every 3 days to female rats one week prior to pairing with untreated males, and dosing was continued through mating to gestation day 17. Maternal toxicity included a transient histamine-release response (hypoactivity, ataxia, flushed extremities, dilated pupils and/or swollen facial area) at rezafungin doses of 15 mg/kg and above. No adverse embryofetal outcomes were observed in rat pups at rezafungin doses of 45 mg/kg, equivalent to 5 times the clinical exposure based on AUC comparisons. No adverse outcomes were observed when rezafungin was dosed intravenously once every 3 days to pregnant rabbits during the period of organogenesis (GD 7 to 19) at doses up to 35 mg/kg (approximately 3 times the clinical exposure) despite maternal toxicity (reduced bodyweight gain). In a pre- and post-natal study, there were no adverse effects on offspring growth, maturation, or measures of neurobehavioral or reproductive function in rats administered rezafungin intravenously once every 3 days from 1 week prior to mating through weaning (LD20), at doses up to 45 mg/kg/day (about 5 times the recommended human dose based on AUC comparisons).

The safety and effectiveness of REZZAYO have been established in pediatric patients 12 years of age or older who have limited or no alternative options for the treatment of candidemia and invasive candidiasis. Use of REZZAYO in this age group, for this indication, is supported by evidence from adequate and well-controlled studies of REZZAYO in adults [weight range: 34 to 154.5 kg], along with additional population pharmacokinetic analyses demonstrating that age or body weight had no clinically meaningful effect on rezafungin exposures. There have been no clinical studies conducted with REZZAYO in pediatric patients [see Dosage and Administration ( 2.1 ), Clinical Pharmacology ( 12.3 ), and Clinical Studies ( 14 )] . The safety and effectiveness of REZZAYO have not been established in pediatric patients younger than 12 years old.

Of the 151 rezafungin-treated patients at the proposed dose in Trials 1 and 2, 64 patients (42%) were 65 years of age and older, while 26 patients (17%) were 75 years of age and older. Clinical studies of REZZAYO did not include sufficient numbers of older adult patients to determine if patients 65 years and older respond differently than younger adult patients.

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

No cases of overdose were reported during the clinical studies. Rezafungin is highly protein bound and not anticipated to be dialyzable.