FDA label 4c7649f3-4d38-47e2-aa0d-2ed606bb930a

5 WARNINGS AND PRECAUTIONS Coagulation test interference: ORBACTIV has been shown to artificially prolong aPTT for up to 120 hours, and may prolong PT and INR for up to 12 hours and ACT for up to 24 hours. For patients who require aPTT monitoring within 120 hours of ORBACTIV dosing, consider a non-phospholipid dependent coagulation test such as a Factor Xa (chromogenic) assay or an alternative anticoagulant not requiring aPTT. ( 5.1 , 7.2 ) Serious hypersensitivity reactions, including anaphylaxis, have been reported with the use of oritavancin products, including ORBACTIV. Discontinue infusion if signs of acute hypersensitivity occur. Carefully monitor patients with known hypersensitivity to glycopeptides. ( 5.2 ) Infusion Related Reactions: Administer ORBACTIV over 3 hours to minimize infusion. Infusion related reactions have been reported with the glycopeptide class of antimicrobial agents, including oritavancin products (e.g. ORBACTIV). Stopping or slowing the infusion may result in cessation of these reactions. ( 5.3 ) Clostridioides difficile -associated diarrhea: Evaluate patients if diarrhea occurs. ( 5.4 ) Concomitant warfarin use: ORBACTIV has been shown to artificially prolong PT/INR for up to 12 hours ( 5.1 ). Patients should be monitored for bleeding if concomitantly receiving ORBACTIV and warfarin. ( 5.5 ) Osteomyelitis: Institute appropriate alternate antibacterial therapy in patients with confirmed or suspected osteomyelitis. ( 5.6 ) 5.1 Coagulation Test Interference ORBACTIV has been shown to artificially prolong aPTT for up to 120 hours, PT and INR for up to 12 hours, and activated clotting time (ACT) for up to 24 hours following administration of a single 1,200 mg dose by binding to and preventing action of the phospholipid reagents commonly used in laboratory coagulation tests. ORBACTIV has also been shown to elevate D-dimer concentrations up to 72 hours after ORBACTIV administration. For patients who require aPTT monitoring within 120 hours of ORBACTIV 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 [see Contraindications (4.1) and Drug Interactions (7.2) ] . ORBACTIV has no effect on the coagulation system in vivo. 5.2 Hypersensitivity Serious hypersensitivity reactions, including anaphylaxis, have been reported with the use of oritavancin products, including ORBACTIV. If an acute hypersensitivity reaction occurs during ORBACTIV infusion, discontinue ORBACTIV immediately and institute appropriate supportive care. Before using ORBACTIV, inquire carefully about previous hypersensitivity reactions to glycopeptides. Due to the possibility of cross-sensitivity, carefully monitor for signs of hypersensitivity during ORBACTIV infusion in patients with a history of glycopeptide allergy. In the Phase 3 ABSSSI clinical trials, the median onset of hypersensitivity reactions in ORBACTIV-treated patients was 1.2 days and the median duration of these reactions was 2.4 days [see Adverse Reactions (6.1) ] . 5.3 Infusion Related Reactions ORBACTIV is administered as a single dose by intravenous infusion, using a total infusion time of 3 hours to minimize the risk of infusion-related reactions. Infusion related reactions have been reported with the glycopeptide class of antimicrobial agents, including oritavancin products (e.g. ORBACTIV), including flushing of the upper body, urticaria, pruritus and/or rash [see Adverse Reactions (6.1) ] . Infusion reactions characterized by chest pain, back pain, chills and tremor have been observed with the use of ORBACTIV, including after the administration of more than one dose of ORBACTIV during a single course of therapy. Stopping or slowing the infusion may result in cessation of these reactions. The safety and effectiveness of more than one dose of ORBACTIV during a single course of therapy have not been established [see Dosage and Administration (2.2) ]. 5.4 Clostridioides difficile -associated Diarrhea Clostridioides difficile -associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial drugs, including ORBACTIV, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile . C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antibacterial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated . 5.5 Potential Risk of Bleeding with Concomitant Use of Warfarin ORBACTIV has been shown to artificially prolong prothrombin time (PT) and international normalized ratio (INR) for up to 12 hours, making the monitoring of the anticoagulation effect of warfarin unreliable up to 12 hours after an ORBACTIV dose [see Warnings and Precautions (5.1 )] . Patients should be monitored for bleeding if concomitantly receiving ORBACTIV and warfarin [see Drug Interactions (7.1) ] . 5.6 Osteomyelitis In Phase 3 ABSSSI clinical trials, more cases of osteomyelitis were reported in the ORBACTIV treated arm than in the vancomycin-treated arm. Monitor patients for signs and symptoms of osteomyelitis. If osteomyelitis is suspected or diagnosed, institute appropriate alternate antibacterial therapy [see Adverse Reactions (6.1) ] . 5.7 Development of Drug Resistant Bacteria Prescribing ORBACTIV in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria [see Patient Counseling Information (17) ] .

6 ADVERSE REACTIONS 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 ORBACTIV were headache, nausea, vomiting, limb and subcutaneous abscesses, and diarrhea. ( 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 ORBACTIV cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. ORBACTIV 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 ORBACTIV and 983 patients treated with intravenous vancomycin for 7 to 10 days. The median age of patients treated with ORBACTIV was 45.6 years, ranging between 18 and 89 years of age with 8.8% ≥65 years of age. Patients treated with ORBACTIV 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 ORBACTIV 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 ORBACTIV 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 ORBACTIV in the pooled ABSSSI clinical trials were: headache, nausea, vomiting, limb and subcutaneous abscesses, and diarrhea. In the pooled ABSSSI clinical trials, ORBACTIV 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 ORBACTIV in the pooled ABSSSI clinical trials. There were 540 (55.3%) patients in the ORBACTIV 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 ORBACTIV in the Pooled ABSSSI Clinical Trials Adverse Reactions ORBACTIV 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 ORBACTIV-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 6.2 Immunogenicity There is potential for immunogenicity following administration of oritavancin products, including ORBACTIV. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Because several factors in an assay may influence the observed incidence of antibody positivity, comparison of the incidence of antibodies to oritavancin in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. Positive indirect and direct antiglobulin tests (IAT/DAT) were noted with the administration of ORBACTIV and KIMYRSA (hereinafter referred to as another oritavancin product) in studies with healthy subjects and patients with ABSSSI. In a randomized, open-label, multi-center ABSSSI study, positive antiglobulin tests were reported in 9.6% (5/52) of subjects who received ORBACTIV and 2% (1/50) of subjects who received another oritavancin product. Oritavancin-dependent RBC antibodies were detected when tested in the presence of drug for three subjects in the ORBACTIV group. In a multiple dose study with ORBACTIV in healthy volunteers, 90% (9/10) of subjects had a positive IAT 14 days after the second infusion. In a healthy volunteer study, 66% (22/32) of subjects receiving another oritavancin product had a positive IAT 15 days after receiving dosing and one subject had a positive DAT at 8 days after dosing. There were no reports of hemolysis in subjects who had positive IAT/DAT. If hemolytic anemia develops following treatment with ORBACTIV provide appropriate care. Positive IAT may interfere with cross-matching before blood transfusion [see Drug Interactions (7.2) ].

<table ID="t1" width="90%"><caption>Table 1: Incidence of Selected Adverse Reactions Occurring in &#x2265;1.5% of Patients Receiving ORBACTIV in the Pooled ABSSSI Clinical Trials</caption><col width="50%" align="left" valign="top"/><col width="25%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><thead><tr><th align="center">Adverse Reactions</th><th>ORBACTIV N=976 (%)</th><th>Vancomycin N=983 (%)</th></tr></thead><tbody><tr><td colspan="3"><content styleCode="bold">Gastrointestinal disorders</content></td></tr><tr><td>Diarrhea</td><td>36 (3.7)</td><td>32 (3.4)</td></tr><tr><td>Nausea</td><td>97 (9.9)</td><td>103 (10.5)</td></tr><tr><td>Vomiting</td><td>45 (4.6)</td><td>46 (4.7)</td></tr><tr><td colspan="3"><content styleCode="bold">Nervous system disorders</content></td></tr><tr><td>Dizziness</td><td>26 (2.7)</td><td>26 (2.6)</td></tr><tr><td>Headache</td><td>69 (7.1)</td><td>66 (6.7)</td></tr><tr><td colspan="3"><content styleCode="bold">General disorders and administration</content></td></tr><tr><td>Infusion site phlebitis</td><td>24 (2.5)</td><td>15 (1.5)</td></tr><tr><td>Infusion site reaction</td><td>19 (1.9)</td><td>34 (3.5)</td></tr><tr><td colspan="3"><content styleCode="bold">Infections and infestations</content></td></tr><tr><td>Abscess (limb and subcutaneous)</td><td>37 (3.8)</td><td>23 (2.3)</td></tr><tr><td colspan="3"><content styleCode="bold">Investigations</content></td></tr><tr><td>Alanine aminotransferase increased</td><td>27 (2.8)</td><td>15 (1.5)</td></tr><tr><td>Aspartate aminotransferase increased</td><td>18 (1.8)</td><td>15 (1.5)</td></tr><tr><td colspan="3"><content styleCode="bold">Cardiac disorders</content></td></tr><tr><td>Tachycardia</td><td>24 (2.5)</td><td>11 (1.1)</td></tr></tbody></table>