U.S. FDA APPROVED  DRUGS DURING 2023

Sr.No-  12

------------------------WARNINGS AND PRECAUTIONS---------------------- • 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. (5.1) • Photosensitivity: REZZAYO may cause photosensitivity. Advise patients to use protection from sun exposure and other sources of UV radiation. (5.2) • 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. (5.3) ------------------------------ADVERSE REACTIONS------------------------------- 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. See 17 for PATIENT COUNSELING INFORMATION

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Rezafungin is an echinocandin antifungal drug [see Microbiology(12.4)]. 12.2 Pharmacodynamics 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. Cardiac Electrophysiology Rezafungin does not prolong the QTc interval to any clinically relevant extent at a dose 3.5 times the maximum approved recommended loading dose. 12.3 Pharmacokinetics 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. Rezafungin population PK model derived pharmacokinetics (in patients with candidemia and invasive candidias (IC)) following administration of REZZAYO are provided in Table 3 and presented as mean ± standard deviation (SD). The mean rezafungin AUC0-168h decreased approximately 30% and Cmax 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 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 Reference ID: 5146097 % 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 Cmax= maximum plasma concentration; Cmin= trough plasma concentration; AUC0–168h= area under the plasma concentration-time curve from time zero to 168 hours post dose a Mean ± SD b Time to Cmax is 1hr post-start of infusion (i.e., end of infusion) c Excretion studied in healthy subjects 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. 12.4 Microbiology Mechanism of Action Rezafungin is a semi-synthetic echinocandin. Rezafungin inhibits the 1,3-ß-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-ß-D-glucan, an essential component of the fungal cell wall of many fungi, including Candida species (spp.). Inhibition of 1,3-ß-D-glucan synthesis results in concentration-dependent in vitro fungicidal activity against Candida spp., h

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 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 postnatal 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. Reference ID: 5146097 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). 8.2 Lactation Risk Summary 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. Rezafungin was present in rat milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for REZZAYO and any potential adverse effects on the breastfed infant from REZZAYO or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Infertility Males Based on rat studies, rezafungin could lead to decreased sperm motility, decreased sperm numbers, and increased incidence of sperm with abnormal morphology. The effect of REZZAYO on human fertility is unknown [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of REZZAYO have not been established in pediatric patients. 8.5 Geriatric Use 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. 10 OVERDOSAGE No cases of overdose were reported during the clinical studies. Rezafungin is highly protein bound and not anticipated to be dialyzable. 11 DESCRIPTION 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 Aspergill