KIMYRSA

KIMYRSA (oritavancin) for injection contains oritavancin diphosphate, a semisynthetic lipoglycopeptide antibacterial drug for intravenous infusion. The chemical name for oritavancin is [4"R]-22- O -(3-amino-2,3,6-trideoxy-3- C -methyl-α-L- arabino -hexopyranosyl)- N 3''-[(4'-chloro[1,1'-biphenyl]-4-yl)methyl] vancomycin phosphate [1:2] [salt]. The empirical formula of oritavancin diphosphate is C 86 H 97 N 10 O 26 Cl 3 •2H 3 PO 4 and the molecular weight is 1989.09. The chemical structure is represented below: ∙2H 3 PO 4 KIMYRSA for injection is supplied as a sterile white to off-white or pink lyophilized powder in a single-dose clear glass vial that contains 1,200 mg of oritavancin (equivalent to 1331.16 mg oritavancin diphosphate) and the following inactive ingredients: hydroxypropyl-β-cyclodextrin (HPβCD) (2400 mg), mannitol (800 mg) and phosphoric acid or sodium hydroxide (to adjust pH 4.0 to 6.0). The vial is reconstituted with sterile water for injection and further diluted with 0.9% sodium chloride injection or 5% dextrose in sterile water (D5W) for intravenous infusion. Both the reconstituted solution and the diluted solution for infusion should be a clear, colorless to pink solution, free of visible particles [see Dosage and Administration (2.3) ] . Chemical Structure

KIMYRSA is a lipoglycopeptide antibacterial drug indicated for the treatment of adult patients with acute bacterial skin and skin structure infections caused or suspected to be caused by susceptible isolates of designated Gram-positive microorganisms. ( 1.1 ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of KIMYRSA and other antibacterial drugs, KIMYRSA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. ( 1.2 ) 1.1 Acute Bacterial Skin and Skin Structure Infections KIMYRSA ® is indicated for the treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following Gram-positive microorganisms: Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant isolates), Streptococcus pyogenes , Streptococcus agalactiae , Streptococcus dysgalactiae , Streptococcus anginosus group (includes S. anginosus , S. intermedius , and S. constellatus ), and Enterococcus faecalis (vancomycin-susceptible isolates only). 1.2 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of KIMYRSA and other antibacterial drugs, KIMYRSA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

There are two oritavancin products (KIMYRSA and ORBACTIV ® , another oritavancin product) that have differences in dose strength, duration of infusion and preparation instructions, including reconstitution and dilution instructions and compatible diluents ( 2.1 , 2.2 , 2.3 , 2.4 ) Administer 1,200 mg of KIMYRSA as a single dose by intravenous infusion over 1 hour. ( 2.1 , 5.3 ) Carefully follow the recommended dosage and dose preparation instructions for KIMYRSA in the full prescribing information. ( 2.1 , 2.2 , 2.3 ) 2.1 Dosage and Administration Overview There are two oritavancin products (KIMYRSA and ORBACTIV ® , another oritavancin product) that: Are supplied in different dose strengths of oritavancin [see Dosage Forms and Strengths (3) ] . Have different recommended durations of infusion [see Dosage and Administration (2.2) ]. Have different preparation instructions, including differences in reconstitution, dilution, and compatible diluents [see Dosage and Administration (2.3 , 2.4) ] . Carefully follow the recommended dosage and dose preparation instructions for KIMYRSA in this prescribing information (PI) [see Dosage and Administration (2.1 , 2.2 , 2.3 , 2.4) ]. Refer to the ORBACTIV prescribing information for relevant information of the other oritavancin product. 2.2 Recommended Dosage The recommended dosage of KIMYRSA is 1,200 mg administered as a single dose by intravenous infusion over 1 hour in patients 18 years and older [see Warnings and Precautions (5.3) ] . 2.3 Preparation of KIMYRSA for Intravenous Infusion There are two oritavancin products (KIMYRSA and ORBACTIV, another oritavancin product) that have differences in dose strengths, duration of infusion, reconstitution and dilution instructions, and compatible diluents. Carefully follow the reconstitution, and dilution instructions with the appropriate compatible diluent for KIMYRSA specified in this prescribing information. Refer to the ORBACTIV prescribing information for relevant information of the other oritavancin product. KIMYRSA is intended for intravenous infusion, only after reconstitution and dilution. One KIMYRSA 1,200 mg single-dose vial needs to be reconstituted and diluted to prepare a single 1,200 mg intravenous dose. Reconstitution : Aseptic technique should be used to reconstitute one KIMYRSA 1,200 mg vial. Add 40 mL of sterile water for injection (SWFI) to reconstitute the vial to provide a 30 mg/mL solution. Gently swirl the contents to avoid foaming and ensure that all KIMYRSA powder is completely dissolved to form a reconstituted solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The reconstituted vial should appear to be a clear, colorless to pink solution, free of visible particles. Dilution : Use 0.9% sodium chloride injection or 5% dextrose in sterile water (D5W) for dilution to prepare the final intravenous solution for infusion. Since no preservative or bacteriostatic agent is present in KIMYRSA, aseptic technique must be used in preparing the final intravenous solution as follows: Withdraw and discard 40 mL from a 250 mL intravenous bag of 0.9% sodium chloride injection or D5W. Withdraw 40 mL of the reconstituted vial of KIMYRSA and add to the intravenous bag of 0.9% sodium chloride injection or D5W to bring the bag volume to 250 mL. This yields a concentration of 4.8 mg/mL. Discard any unused portion of the reconstituted solution remaining in the vial. Storage and Use of Intravenous Solution : Diluted intravenous solution in an infusion bag should be used within 4 hours when stored at room temperature, or used within 12 hours when refrigerated at 2 to 8°C (36 to 46°F). The combined storage time (reconstituted solution in the vial and diluted solution in the bag) and 1 hour infusion time should not exceed 4 hours at room temperature or 12 hours if refrigerated. 2.4 Compatibilities KIMYRSA solution for administration by 1-hour infusion is compatible with: 0.9% sodium chloride injection 5% dextrose in sterile water (D5W) 2.5 Incompatibilities Drugs formulated at a basic or neutral pH may be incompatible with KIMYRSA. KIMYRSA should not be administered simultaneously with commonly used intravenous drugs through a common intravenous port. If the same intravenous line is used for sequential infusion of additional medications, the line should be flushed before and after infusion of KIMYRSA with 0.9% sodium chloride injection or D5W.

Use of intravenous unfractionated heparin sodium is contraindicated for 120 hours (5 days) after KIMYRSA administration. ( 4.1 , 5.1 ) Known hypersensitivity to oritavancin products. ( 4.2 , 5.2 ) 4.1 Intravenous Unfractionated Heparin Sodium Use of intravenous unfractionated heparin sodium is contraindicated for 120 hours (5 days) after KIMYRSA administration because the activated partial thromboplastin time (aPTT) test results may remain falsely elevated for up to 120 hours (5 days) after KIMYRSA administration [see Warnings and Precautions (5.1) and Drug Interactions (7.2) ]. 4.2 Hypersensitivity KIMYRSA is contraindicated in patients with known hypersensitivity to oritavancin products.

The following adverse reactions are also discussed in the Warnings and Precautions section of labeling: Hypersensitivity Reactions [see Warnings and Precautions (5.2) ] Infusion Related Reactions [see Warnings and Precautions (5.3) ] Clostridioides difficile -Associated Diarrhea [see Warnings and Precautions (5.4) ] Osteomyelitis [see Warnings and Precautions (5.6) ] The most common adverse reactions (≥3%) in patients treated with oritavancin products were headache, nausea, vomiting, limb and subcutaneous abscesses, and diarrhea. The adverse reactions occurring in ≥2 patients receiving KIMYRSA were hypersensitivity, pruritus, chills and pyrexia. ( 6.1 ) 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 oritavancin products 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 KIMYRSA has been established from adequate and well-controlled trials of another oritavancin product, ORBACTIV (hereinafter referred to as oritavancin), in patients with ABSSSI, and a study of KIMYRSA in patients with ABSSSI. Oritavancin has been evaluated in two, double-blind, controlled ABSSSI clinical trials, which included 976 adult patients treated with a single 1,200 mg intravenous dose of oritavancin and 983 patients treated with intravenous vancomycin for 7 to 10 days. The median age of patients treated with oritavancin was 45.6 years, ranging between 18 and 89 years of age with 8.8% ≥65 years of age. Patients treated with oritavancin were predominantly male (65.4%), 64.4% were Caucasian, 5.8% were African American, and 28.1% were Asian. Safety was evaluated for up to 60 days after dosing. In the pooled ABSSSI clinical trials, serious adverse reactions were reported in 57/976 (5.8%) patients treated with oritavancin and 58/983 (5.9%) treated with vancomycin. The most commonly reported serious adverse reaction was cellulitis in both treatment groups: 11/976 (1.1%) in oritavancin and 12/983 (1.2%) in the vancomycin arms, respectively. The most commonly reported adverse reactions (≥3%) in patients receiving a single 1,200 mg dose of oritavancin in the pooled ABSSSI clinical trials were: headache, nausea, vomiting, limb and subcutaneous abscesses, and diarrhea. In the pooled ABSSSI clinical trials, oritavancin was discontinued due to adverse reactions in 36/976 (3.7%) of patients; the most common reported reactions leading to discontinuation were cellulitis (4/976, 0.4%) and osteomyelitis (3/976, 0.3%). Table 1 provides selected adverse reactions occurring in ≥1.5% of patients receiving oritavancin in the pooled ABSSSI clinical trials. There were 540 (55.3%) patients in the oritavancin arm and 559 (56.9%) patients in the vancomycin arm, who reported ≥1 adverse reaction. Table 1: Incidence of Selected Adverse Reactions Occurring in ≥1.5% of Patients Receiving Oritavancin in the Pooled ABSSSI Clinical Trials Adverse Reactions Oritavancin N=976 (%) Vancomycin N=983 (%) Gastrointestinal disorders Diarrhea 36 (3.7) 32 (3.4) Nausea 97 (9.9) 103 (10.5) Vomiting 45 (4.6) 46 (4.7) Nervous system disorders Dizziness 26 (2.7) 26 (2.6) Headache 69 (7.1) 66 (6.7) General disorders and administration Infusion site phlebitis 24 (2.5) 15 (1.5) Infusion site reaction 19 (1.9) 34 (3.5) Infections and infestations Abscess (limb and subcutaneous) 37 (3.8) 23 (2.3) Investigations Alanine aminotransferase increased 27 (2.8) 15 (1.5) Aspartate aminotransferase increased 18 (1.8) 15 (1.5) Cardiac disorders Tachycardia 24 (2.5) 11 (1.1) The following selected adverse reactions were reported in oritavancin-treated patients at a rate of less than 1.5%: Blood and lymphatic system disorders : anemia, eosinophilia General disorders and administration site conditions: infusion site erythema, extravasation, induration, pruritus, rash, edema peripheral Immune system disorders: hypersensitivity Infections and infestations: osteomyelitis Investigations: total bilirubin increased, hyperuricemia Metabolism and nutrition disorders: hypoglycemia Musculoskeletal and connective tissue disorders: tenosynovitis, myalgia Respiratory, thoracic and mediastinal disorders: bronchospasm, wheezing Skin and subcutaneous tissue disorders: urticaria, angioedema, erythema multiforme, pruritus, leucocytoclastic vasculitis, rash. KIMYRSA has been evaluated in a randomized, open-label, multi-center ABSSSI study which included 50 adult patients treated with a single 1,200 mg intravenous dose of KIMYRSA administered by intravenous infusion over 1 hour, and 52 patients treated with a single 1,200 mg intravenous dose of oritavancin administered by intravenous infusion over 3 hours. Selected adverse reactions occurring in ≥2 patients receiving either KIMYRSA or oritavancin in the open-label, multi-center ABSSSI study were diarrhea, nausea, vomiting, hypersensitivity, pruritus, chills, headache and pyrexia.

7.1 Effect of KIMYRSA on CYP Substrates A screening drug-drug interaction study indicated that oritavancin is a nonspecific, weak inhibitor (CYP2C9 and CYP2C19) or inducer (CYP3A4 and CYP2D6) of several CYP isoforms [see Clinical Pharmacology (12.3) ] . A drug-drug interaction study that assessed the interaction potential of a single 1,200 mg dose of oritavancin on the pharmacokinetics of S-warfarin (CYP2C9 probe substrate) showed no effect of oritavancin on S-warfarin C max or AUC. Avoid administering KIMYRSA concomitantly with drugs that are predominantly metabolized by one of the affected CYP450 enzymes, as co-administration may increase or decrease concentrations of those drugs. Patients should be closely monitored for signs of toxicity or lack of efficacy if they have been given KIMYRSA while on a potentially affected compound (e.g., patients should be monitored for bleeding if concomitantly receiving KIMYRSA and warfarin). 7.2 Drug-Laboratory Test Interactions Prolongation of Certain Laboratory Coagulation Tests KIMYRSA may artificially prolong certain laboratory coagulation tests (see Table 2 ) by binding to and preventing the action of the phospholipid reagents which activate coagulation in commonly used laboratory coagulation tests [see Contraindications (4.1) and Warnings and Precautions (5.1 , 5.5) ] . For patients who require monitoring of anticoagulation effect within the indicated time after KIMYRSA dosing, a non-phospholipid dependent coagulation test such as a Factor Xa (chromogenic) assay or an alternative anticoagulant not requiring aPTT monitoring may be considered. Oritavancin does not interfere with coagulation in vivo. In addition, oritavancin does not affect tests that are used for diagnosis of Heparin Induced Thrombocytopenia (HIT). Table 2: Coagulation Tests Affected and Unaffected by Oritavancin Elevated by Oritavancin Unaffected by Oritavancin Prothrombin time (PT) up to 12 hours Chromogenic Factor Xa Assay International normalized ratio (INR) up to 12 hours Thrombin Time (TT) Activated partial thromboplastin time (aPTT) up to 120 hours Activated clotting time (ACT) up to 24 hours Silica clot time (SCT) up to 18 hours Dilute Russell's viper venom time (DRVVT) up to 72 hours D-dimer up to 72 hours Positive Indirect and Direct Antiglobulin Tests (IAT/DAT) Positive IAT/DAT were noted with administration of oritavancin products, including KIMYRSA, in studies with healthy volunteers and patients with ABSSSI. Positive IAT may interfere with cross-matching before blood transfusion [see Clinical Pharmacology (12.6) ] .

16.1 How Supplied/Storage KIMYRSA is supplied as a sterile white to off-white or pink lyophilized powder in single-dose clear glass vials containing 1,200 mg of oritavancin. One vial is packaged in a carton to supply a single 1,200 mg dose treatment (NDC 70842-225-01). KIMYRSA vials should be stored at 20ºC to 25ºC (68ºF to 77ºF); excursions permitted to 15ºC to 30ºC (59ºF to 86ºF) [see USP, Controlled Room Temperature (CRT)].