SIVEXTRO

1 INDICATIONS AND USAGE SIVEXTRO is an oxazolidinone antibacterial indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by designated susceptible microorganisms in adult and pediatric patients (at least 26 weeks gestational age and weighing at least 1 kg) ( 1.1 ) Usage to Reduce Development of Drug-Resistant Bacteria To reduce the development of drug-resistant bacteria and maintain the effectiveness of SIVEXTRO and other antibacterial drugs, SIVEXTRO should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. 1.1 Acute Bacterial Skin and Skin Structure Infections SIVEXTRO ® is indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following gram-positive microorganisms: Staphylococcus aureus (including methicillin-resistant [MRSA] and methicillin-susceptible [MSSA] isolates), Streptococcus pyogenes , Streptococcus agalactiae , Streptococcus anginosus Group (including Streptococcus anginosus , Streptococcus intermedius , and Streptococcus constellatus ), and Enterococcus faecalis , in adult and pediatric patients (at least 26 weeks gestational age and weighing at least 1 kg). 1.2 Usage to Reduce Development of Drug-Resistant Bacteria To reduce the development of drug-resistant bacteria and maintain the effectiveness of SIVEXTRO and other antibacterial drugs, SIVEXTRO should be used only to treat or prevent infections that are proven or strongly suspected to be caused by 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.

2 DOSAGE AND ADMINISTRATION Do not administer SIVEXTRO Tablets to pediatric patients weighing less than 35 kg. ( 2.1 ) Adult Patients Intravenous and Oral Dosage : 200 mg administered once daily orally or as an intravenous (IV) infusion over 1 hour for 6 days as specified in Table 1 in the full prescribing information. ( 2.2 ) Pediatric Patients Intravenous Dosage (at least 26 weeks gestational age and weighing at least 1 kg): Weight-based dosing as an intravenous infusion as specified in Table 2 in the full prescribing information. ( 2.3 ) Pediatric Patients Oral Dosage (weighing greater than or equal to 35 kg): Weight-based dosing as an oral tablet administered once daily as specified in Table 3 in the full prescribing information. ( 2.3 ) 2.1 Important Administration Instructions for Pediatric Patients Weighing Less than 35 kg Do not administer SIVEXTRO Tablets to pediatric patients weighing less than 35 kg [see Dosage and Administration 2.3 ]. 2.2 Recommended Dosage for Adult Patients The recommended dosage of SIVEXTRO is 200 mg administered once daily for six (6) days either as an oral tablet (with or without food) or as an intravenous (IV) infusion in adult patients. The recommended dosage and administration of SIVEXTRO in adult patients are described in Table 1 . Table 1: Recommended Dosage of SIVEXTRO for Adult Patients Infection Route Dose Frequency Infusion Time Duration of Treatment Acute Bacterial Skin and Skin Structure Infections (ABSSSI) Intravenous 200 mg Once daily 1 hour 6 days Oral 200 mg Once daily Not Applicable No dose adjustment is necessary when changing from intravenous to oral SIVEXTRO. 2.3 Recommended Dosage for Pediatric Patients Recommended Dosage of SIVEXTRO for Injection for Pediatric Patients: Intravenous Dosage The recommended intravenous dosage of SIVEXTRO for Injection for pediatric patients (at least 26 weeks gestational age and weighing at least 1 kg) is presented in Table 2 . Table 2: Recommended Intravenous Dosage of SIVEXTRO for Injection for Pediatric Patients Weight Band (kg) Dose Frequency Infusion Time Duration of Treatment Pediatric Patients Weighing Less than 2 kg 1 to less than 2 Recommended Dosage for 1 kg to less than 2 kg is based on actual body weight. 3 mg/kg Twice daily 1 hour 6 days Pediatric Patients Weighing at Least 2 kg 2 to less than 3 6 mg Twice daily 1 hour 6 days 3 to less than 6 12 mg 6 to less than 10 20 mg 10 to less than 14 30 mg 14 to less than 20 40 mg 20 to less than 35 60 mg Pediatric Patients Weighing at Least 35 kg Greater than or equal to 35 200 mg Once daily 1 hour 6 days Recommended Dosage of SIVEXTRO Tablets for Pediatric Patients: Oral Dosage The recommended oral dosage of SIVEXTRO Tablets for pediatric patients is presented in Table 3 . SIVEXTRO Tablets can be administered with or without food. Do not administer SIVEXTRO Tablets to pediatric patients weighing less than 35 kg. Table 3: Recommended Oral Tablet Dosage of SIVEXTRO for Pediatric Patients Weight Band (kg) Dose Frequency Duration of Treatment Greater than or equal to 35 200 mg Once daily 6 days No dose adjustment is necessary when changing from intravenous to oral SIVEXTRO. 2.4 Recommendations Regarding Missed Doses(s) For Once Daily Oral Dosing of SIVEXTRO Tablets If patients miss a dose, administer the dose as soon as possible anytime up to 8 hours prior to their next scheduled dose. If less than 8 hours remain before the next dose, instruct the patients to wait until their next scheduled dose. 2.5 Preparation and Administration of Intravenous Solution SIVEXTRO is supplied as a sterile, lyophilized powder for injection in single-dose vials of 200 mg. Each 200 mg vial must be reconstituted with Sterile Water for Injection and subsequently diluted with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. SIVEXTRO vials contain no antimicrobial preservatives and are intended for single dose only. Discard any unused portion. Preparation of SIVEXTRO for Injection Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The contents of the vial should be reconstituted using aseptic technique as follows: Note: To minimize foaming, AVOID vigorous agitation or shaking of the vial during or after reconstitution. For Adults and Pediatric Patients Weighing at Least 35 kg: Reconstitute the SIVEXTRO vial with 4 mL of Sterile Water for Injection to provide a concentration of 50 mg/mL in each vial. Gently swirl the contents and let the vial stand until the cake has completely dissolved and any foam disperses. Inspect the vial to ensure the solution contains no particulate matter and no cake or powder remains attached to the sides of the vial. If necessary, invert the vial to dissolve any remaining powder and swirl gently to prevent foaming. The reconstituted solution is clear and colorless to pale-yellow in color; the total time from reconstitution to the end of administration should not exceed 24 hours at either room temperature or under refrigeration at 2°C to 8°C (36°F to 46°F). Tilt the upright vial and insert a syringe with appropriately sized needle into the bottom corner of the vial and remove 4 mL of the reconstituted solution for the 200 mg dose. Do not invert the vial during extraction. The reconstituted solution must be further diluted in 250 mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Slowly inject the required volume of reconstituted solution as determined in Step 2 into a 250 mL bag of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Invert the bag gently to mix. Do NOT shake the bag as this may cause foaming. For Pediatric Patients Weighing Less than 35 kg: Reconstitute the SIVEXTRO vial with 4 mL of Sterile Water for Injection to provide a concentration of 50 mg/mL in each vial. Gently swirl the contents and let the vial stand until the cake has completely dissolved and any foam disperses. Inspect the vial to ensure the solution contains no particulate matter and no cake or powder remains attached to the sides of the vial. If necessary, invert the vial to dissolve any remaining powder and swirl gently to prevent foaming. The reconstituted solution is clear and colorless to pale-yellow in color; the total time from reconstitution to the end of administration should not exceed 24 hours at either room temperature or under refrigeration at 2°C to 8°C (36°F to 46°F). Prepare a stock solution (100 mL of 0.8 mg/mL tedizolid phosphate): Tilt the upright vial and insert a syringe with appropriately sized needle into the bottom corner of the vial and remove 1.6 mL of the reconstituted solution and add it to an infusion bag containing 98.4 mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Do not invert the vial during extraction. Prepare the required volume of stock solution for infusion: Refer to Table 4 to convert the dose in mg to the appropriate volume of stock solution to be administered. Transfer this volume of stock solution to an adequately sized infusion bag or infusion syringe. It may be necessary to round to the nearest graduation mark of an appropriately sized syringe for smaller volumes. The total time from reconstitution to the end of administration should not exceed 24 hours at either room temperature or under refrigeration at 2°C to 8°C (36°F to 46°F). Table 4: Preparation of SIVEXTRO for Injection for Pediatric Patients Weighing 1 kg to Less than 35 kg from the 100 mL Stock Solution of 0.8 mg/mL Tedizolid Phosphate Body Weight (kg) Amount of SIVEXTRO per dose (given twice daily) Volume of stock solution (0.8 mg/mL) to be transferred to an adequately sized infusion bag or infusion syringe Pediatric Patients Weighing Less than 2 kg 1 to less than 2 3 mg/kg Volume (mL) = Weight (kg) x 3.75 mL/kg Pediatric Patients Weighing at Least 2 kg 2 to less than 3 6 mg 7.5 mL 3 to less than 6 12 mg 15 mL 6 to less than 10 20 mg 25 mL 10 to less than 14 30 mg 37.5 mL 14 to less than 20 40 mg 50 mL 20 to less than 35 60 mg 75 mL Administration of SIVEXTRO for Injection Administer SIVEXTRO for Injection as an intravenous infusion only. Do not administer as an intravenous push or bolus. Do not mix SIVEXTRO for Injection with other drugs when administering. It is not intended for intra-arterial, intramuscular, intrathecal, intraperitoneal, or subcutaneous administration. The intravenous bag containing the reconstituted and diluted intravenous solution should be inspected visually for particulate matter prior to administration. Discard if visible particles are observed. The resulting solution is clear and colorless to pale-yellow in color. After reconstitution and dilution, SIVEXTRO for Injection is to be administered via intravenous infusion using a total time of 1 hour. The total time from reconstitution to the end of administration of SIVEXTRO for Injection should not exceed 24 hours at either room temperature or under refrigeration at 2°C to 8°C (36°F to 46°F). Discard unused portion. 2.6 Compatible Intravenous Solutions SIVEXTRO is compatible with 0.9% Sodium Chloride Injection, USP and 5% Dextrose Injection, USP. Limited data are available on the compatibility of SIVEXTRO for Injection with other intravenous substances, additives or other medications and they should not be added to SIVEXTRO single-dose vials or infused simultaneously. If the same intravenous line is used for sequential infusion of several different drugs, the line should be flushed before and after infusion of SIVEXTRO with 0.9% Sodium Chloride Injection, USP. 2.7 Incompatibilities SIVEXTRO for Injection is incompatible with any solution containing divalent cations (e.g., Ca 2+ , Mg 2+ ), including Lactated Ringer’s Injection and Hartmann’s Solution.

4 CONTRAINDICATIONS None. None ( 4 )

5 WARNINGS AND PRECAUTIONS Serotonin Syndrome: Monitor patients taking SIVEXTRO concomitantly with serotonergic agents for signs of serotonin syndrome. If signs or symptoms of serotonin syndrome occur, consider discontinuing SIVEXTRO and/or concomitant serotonergic agents. ( 5.1 ) Patients with neutropenia: The safety and efficacy of SIVEXTRO in patients with neutropenia (neutrophil counts <1000 cells/mm 3 ) have not been adequately evaluated. In an animal model of infection, the antibacterial activity of SIVEXTRO was reduced in the absence of granulocytes. Consider alternative therapies in neutropenic patients. ( 5.2 ) Clostridioides difficile -Associated Diarrhea: Evaluate if diarrhea occurs. ( 5.3 ) 5.1 Serotonin Syndrome Spontaneous reports of serotonin syndrome have been observed with the co-administration of oxazolidinones, including SIVEXTRO, and serotonergic agents. Commonly used serotonergic agents include serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, buspirone, serotonin 5-HT1 receptor agonists (triptans), and opioids, including meperidine. Symptoms associated with serotonin syndrome may include hyperthermia, diaphoresis, agitation, hyperreflexia, clonus, pyrexia, opsoclonus, muscle rigidity, tremor, and hypertonia. Monitor patients for the emergence of serotonin syndrome with the concomitant use of SIVEXTRO and serotonergic agents. If signs or symptoms of serotonin syndrome occur, consider discontinuing SIVEXTRO and/or concomitant serotonergic agents as clinically appropriate and initiate supportive treatment. Inform patients of the increased risk of serotonin syndrome when SIVEXTRO is used concomitantly with serotonergic agents. 5.2 Patients with Neutropenia The safety and efficacy of SIVEXTRO in patients with neutropenia (neutrophil counts <1000 cells/mm 3 ) have not been adequately evaluated. In an animal model of infection, the antibacterial activity of SIVEXTRO was reduced in the absence of granulocytes [see Clinical Pharmacology (12.2) ] . Alternative therapies should be considered when treating patients with neutropenia and ABSSSI. 5.3 Clostridioides difficile -Associated Diarrhea Clostridioides difficile -associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents including SIVEXTRO, with severity ranging from mild diarrhea to fatal colitis. Treatment with antibacterial agents can alter 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 drug use. Careful medical history is necessary because CDAD has been reported to occur more than two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, antibacterial use not directed against C. difficile should be discontinued, if possible. Appropriate measures such as fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated. 5.4 Development of Drug-Resistant Bacteria Prescribing SIVEXTRO in the absence of a proven or strongly suspected bacterial infection or prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

7 DRUG INTERACTIONS SIVEXTRO (when administered orally) can increase the plasma concentrations of orally administered Breast Cancer Resistance Protein (BCRP) substrates. Monitor for adverse reactions related to the concomitant BCRP substrates if coadministration cannot be avoided. ( 7 , 12.3 ) SIVEXTRO has the potential for interaction with serotonergic agents. ( 5.1 , 7 ) 7.1 Membrane Transporters Orally administered SIVEXTRO inhibits Breast Cancer Resistance Protein (BCRP) in the intestine, which can increase the plasma concentrations of orally administered BCRP substrates, and the potential for adverse reactions. If possible, an interruption in the treatment of the co-administered BCRP substrate medicinal product should be considered during treatment with SIVEXTRO, especially for BCRP substrates with a narrow therapeutic index (e.g., methotrexate or topotecan). If coadministration cannot be avoided, monitor for adverse reactions related to the concomitantly administered BCRP substrates, including rosuvastatin [see Clinical Pharmacology (12.3) ]. 7.2 Serotonergic Agents In postmarketing experience, there have been reports of serotonin syndrome in patients taking SIVEXTRO with serotonergic agents [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Serotonin Syndrome [see Warnings and Precautions (5.1) ] Clostridioides difficile -Associated Diarrhea [see Warnings and Precautions (5.3) ] The most common adverse reactions (≥2%) in adult patients are nausea, headache, diarrhea, infusion- or injection-related adverse reactions, vomiting, and dizziness. ( 6.1 ) The most common adverse reactions (>2%) in pediatric patients (12 years to less than 18 years of age) are phlebitis and increased hepatic transaminases. ( 6.1 ) The most common adverse reactions (>2%) in pediatric patients (less than 12 years of age) are infusion- or injection-related adverse reactions and vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 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 clinical trials of a drug cannot be compared directly to rates from clinical trials of another drug and may not reflect rates observed in practice. Clinical Trials Experience in Adult Patients Adverse reactions were evaluated for 1425 adult patients treated with SIVEXTRO in two Phase 2 and four Phase 3 clinical trials (three Phase 3 trials for 6 days of therapy and one Phase 3 trial for 7-21 days of therapy). The median age of adult patients treated with SIVEXTRO in the Phase 2 and Phase 3 trials was 44 years, ranging between 17 and 94 years old. The majority of adult patients treated with SIVEXTRO were male (66%) and White (67%). Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation in Adults Serious adverse reactions occurred in 37/1425 (2.6%) of adult patients treated with SIVEXTRO and in 25/1000 (2.5%) of adult patients treated with the comparator. SIVEXTRO was discontinued due to an adverse reaction in 14/1425 (1%) of adult patients and the comparator was discontinued due to an adverse reaction in 13/1000 (1.3%) of adult patients. Most Common Adverse Reactions in Adults The most common adverse reactions in adult patients treated with SIVEXTRO were nausea (7.1%), headache (4.5%), diarrhea (3.6%), vomiting (2.7%), and dizziness (1.6%). The median time of onset of adverse reactions was 5 days for both SIVEXTRO and linezolid with 12% occurring on the second day of treatment in both treatment groups. Table 5 lists selected adverse reactions occurring in at least 2% of adult patients treated with SIVEXTRO in clinical trials. Table 5: Selected Adverse Reactions Occurring in ≥2% of Adult Patients Receiving SIVEXTRO in the Pooled Phase 3 ABSSSI Clinical Trials Adverse Reactions Pooled Phase 3 ABSSSI Clinical Trials SIVEXTRO (200 mg oral/intravenous once daily for 6 days) (N=1037) Linezolid (600 mg oral/intravenous twice daily for 10 days) (N=1000) Gastrointestinal Disorders Nausea 7% 10% Diarrhea 4% 5% Vomiting 3% 5% Nervous System Disorder Headache 5% 5% Dizziness 2% 2% Infusion- or Injection-Related Adverse Reactions Includes adverse reactions in the following body system or organ classes: General disorders and administration site conditions, infections and infestations, injury, poisoning and procedural complications, and vascular disorders, including but not limited to, phlebitis, injection- or infusion-site pain, injection- or infusion-site swelling, injection-site reaction, injection-site erythema, injection-site induration, and infusion-related reaction. 4% 2% The following selected adverse reactions were reported in SIVEXTRO-treated adult patients at a rate of less than 2% in these clinical trials: Blood and Lymphatic System Disorders: anemia Cardiovascular: palpitations, tachycardia Eye Disorders: asthenopia, vision blurred, visual impairment, vitreous floaters Immune System Disorders: drug hypersensitivity Infections and Infestations: Clostridioides difficile colitis, oral candidiasis, vulvovaginal mycotic infection Investigations: hepatic transaminases increased (ALT increased, AST increased), gamma-glutamyltransferase (GGT) increased, white blood cell count decreased Nervous System Disorders: hypoesthesia, paresthesia, VII th nerve paralysis Psychiatric Disorders: insomnia Skin and Subcutaneous Tissue Disorders: pruritus, urticaria, dermatitis Vascular Disorders: flushing, hypertension Laboratory Parameters Hematology laboratory abnormalities that were determined to be potentially clinically significant in the pooled Phase 3 ABSSSI clinical trials are provided in Table 6 . Table 6: Potentially Clinically Significant Lowest Laboratory Values in the Pooled Phase 3 ABSSSI Clinical Trials in Adults Laboratory Assay Potentially Clinically Significant Values <75% (<50% for absolute neutrophil count) of lower limit of normal (LLN) for post-baseline measurements , Represents laboratory values within two days after the last dose of active drug SIVEXTRO (200 mg oral/intravenous once daily for 6 days) (N) Number of subjects with at least one post-baseline test result that are within two days after the last dose of active drug Linezolid (600 mg oral/intravenous twice daily for 10 days) (N) M = male; F = female Hemoglobin (<10.1 g/dL [M]) (<9 g/dL [F]) (994) 3.4% (957) 3.4% Platelet count (<112 × 10 3 /mm 3 ) (989) 2.1% (950) 3.8% Absolute neutrophil count (<0.8 × 10 3 /mm 3 ) (980) 0.4% (941) 0.6% Myelosuppression Phase 1 studies conducted in healthy adults exposed to SIVEXTRO for 21 days showed a possible dose and duration effect on hematologic parameters beyond 6 days of treatment. In the Phase 3 trials, clinically significant changes in these parameters were generally similar for both treatment arms (see Table 6 ). In postmarketing experience, thrombocytopenia has been reported in patients treated with SIVEXTRO. In one postmarketing report, patients who experienced thrombocytopenia were treated with tedizolid for a median duration of 26.5 days. A duration of treatment beyond 6 days is not approved . Peripheral and Optic Neuropathy Peripheral and optic neuropathy have been described in patients treated with another member of the oxazolidinone class for longer than 28 days. In Phase 3 trials in adults, reported adverse reactions for peripheral neuropathy and optic nerve disorders were similar between both treatment arms (peripheral neuropathy 1.2% vs. 0.7% for tedizolid phosphate and linezolid, respectively; optic nerve disorders 0.3% vs. 0.1%, respectively). Clinical Trials Experience in Pediatric Patients SIVEXTRO was evaluated in 166 pediatric patients with ABSSSI in two randomized, active-controlled clinical trials, including one in patients aged 12 years to less than 18 years and one in patients aged 4 months to less than 12 years (Pediatric Trial 1 and Pediatric Trial 2, respectively). Additionally, SIVEXTRO was evaluated in 47 pediatric patients less than 2 years of age with a suspected or confirmed gram-positive bacterial infection in an open-label clinical trial (pediatric Trial 3). Pediatric Trial 1 Adverse Reactions Pediatric Trial 1 was a randomized, active-controlled, single-blind clinical trial that enrolled pediatric patients aged 12 to less than 18 years with ABSSSI. A total of 91 pediatric patients were treated with IV and/or oral SIVEXTRO 200 mg for 6 days and 29 patients were treated with a comparator agent for 10 days. The majority of pediatric patients treated with SIVEXTRO were male (64%) and white (88%). Serious adverse reactions occurred in 1/91 (1%) of pediatric patients treated with SIVEXTRO and in none of the 29 patients treated with the comparator. Adverse reactions leading to discontinuation occurred in 1 (1%) pediatric patient in the SIVEXTRO arm and in none in the comparator arm. The most common adverse reactions occurring in those receiving SIVEXTRO in Pediatric Trial 1 were phlebitis (3%), increased hepatic transaminases (alanine aminotransferase, aspartate aminotransferase) (3%), anemia (1%), and vomiting (1%). Laboratory Parameters Table 7: Potentially Clinically Significant Lowest Laboratory Values in the ABSSSI Clinical Trial in Pediatric Patients (12 to <18 years) Laboratory Assay Potentially Clinically Significant Values <75% (<50% for absolute neutrophil count) of lower limit of normal (LLN) for post-baseline measurements , Represents laboratory values within two days after the last dose of active drug SIVEXTRO (200 mg oral/intravenous once daily for 6 days) (N) Number of subjects with at least one post-baseline test result that are within two days after the last dose of active drug Comparators 5 IV and 4 oral comparators selected per local standard of care (for 10 days) (N) M = male; F = female Hemoglobin (<10.1 g/dL [M]) (<9 g/dL [F]) (85) 2.4% (26) 0.0% Platelet count (<112 × 10 3 /mm 3 ) (82) 1.2% (26) 0.0% Absolute neutrophil count (<0.8 × 10 3 /mm 3 ) (85) 0.0% (26) 0.0% Pediatric Trial 2 Pediatric Trial 2 was a randomized, active-controlled, single-blind clinical trial that enrolled pediatric patients aged 4 months to less than 12 years with ABSSSI. A total of 75 patients were treated with IV and/or oral SIVEXTRO for 6 to 10 days and 25 were treated with a comparator agent for 10 to 14 days. The oral suspension formulation (currently not an approved formulation) was used in the clinical trial for those receiving oral therapy [see Clinical Studies (14.1) ]. The majority of patients treated with SIVEXTRO were male (53%) and white (77%), with a median age of 7 years and range of 0.3 to 11 years. The most common adverse reactions occurring in >2% of patients receiving SIVEXTRO in Pediatric Trial 2 were infusion- or injection-related adverse reactions (including catheter site pain, catheter occlusion, infusion site extravasation, phlebitis; 5%), and vomiting (4%). Potentially clinically significant laboratory abnormalities in Pediatric Trial 2 included one patient treated with SIVEXTRO who developed thrombocytopenia with platelet count less than 100 × 10 3 /mm 3 . Pediatric Trial 3 Pediatric Trial 3 was an open-label, pharmacokinetic and safety trial enrolling 47 pediatric patients less than 2 years of age as follows: ages 28 days to less than 2 years (N=14), term neonates from birth to less than 28 days (N=16), and pre-term neonates (gestational age ≥ 26 weeks) from birth to less than 28 days (N=17). In this single-arm trial, 39 patients aged less than 2 years with a suspected or confirmed gram-positive bacterial infection received a single-dose of IV or oral SIVEXTRO and 8 patients aged less than 28 days with a suspected or confirmed gram-positive bacterial infection received multiple doses of IV SIVEXTRO for 3 days. The majority of patients were male (62%) and white (55%), with a median age of 16 days (range 1 day to 608 days). The safety profile observed in this pediatric population was similar to that observed in Pediatric Trials 1 and 2. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of SIVEXTRO. 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. Blood and Lymphatic System Disorders : thrombocytopenia Nervous system disorders : serotonin syndrome

8.1 Pregnancy Risk Summary Based on animal reproduction studies, SIVEXTRO may cause fetal harm when administered to pregnant women. The available data on the use of SIVEXTRO in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Advise pregnant women of the potential risks to a fetus. Fetal developmental toxicities were observed in mice and rats treated with SIVEXTRO. In embryo-fetal studies in mice and rats, tedizolid phosphate was shown to produce fetal developmental toxicities in mice and maternal toxicity and fetal developmental toxicities in rats. Tedizolid phosphate administered orally during organogenesis to pregnant animals was associated with reduced fetal weights and an increased incidence of costal cartilage anomalies in the absence of maternal toxicity in mice; and maternal toxicity, decreased fetal weights, and increased skeletal variations in rats at plasma exposures approximately 4 and 6 times respectively, the human plasma exposure at the maximum recommended human dose (MRHD) of 200 mg/day. In female rats administered tedizolid phosphate during organogenesis through lactation, there was no evidence of fetal toxicity, developmental delays, or impaired reproduction in the offspring at plasma exposures approximately equivalent to the human plasma exposure at the MRHD. (see Data ) The estimated 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 2-4% and 15-20%, respectively. Data Animal Data In an embryo-fetal development study, tedizolid phosphate administered orally to pregnant mice at doses of 1, 5, and 25 mg/kg/day during organogenesis (Gestational Day [GD] 6 to GD15) was associated with fetal developmental effects occurring in the absence of maternal toxicity, including reduced fetal weights and an increased incidence of costal cartilage anomalies at the high dose (approximately 4-times the human plasma exposure at the MRHD based on plasma AUC comparison). Tedizolid phosphate administered orally at doses of 2.5, 5, and 15 mg/kg/day to pregnant rats during organogenesis (GD6 through GD17) was associated with maternal toxicity (reduced maternal body weights), decreased fetal weights, and increased skeletal variations including reduced ossification of the sternebrae, vertebrae, and skull at the high dose of 15 mg/kg/day (approximately 6-times the human plasma exposure at the MRHD based on plasma AUC comparison). The doses not associated with fetal toxicity in mice and maternal and fetal toxicity in rats were 5 and 2.5 mg/kg/day respectively (for both species approximately equivalent to the human plasma exposure at the MRHD based on plasma AUC comparison). In a pre-postnatal study, oral tedizolid phosphate administered to female rats at doses of 1.25, 2.5, and 3.75 mg/kg/day during gestation and lactation (GD6 through Lactational Day 20) was not associated with maternal toxicity, fetal toxicity, developmental delays, or impaired reproduction at doses up to the high dose of 3.75 mg/kg/day (approximately equivalent to the human plasma exposure at the MRHD based on plasma AUC comparison).