6 ADVERSE REACTIONS The most common adverse reactions (≥2%) are nausea, headache, diarrhea, infusion- or injection-related adverse reactions, vomiting, and dizziness. (6) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Adverse Reactions in Clinical Trials 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. Adverse reactions were evaluated for 1425 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 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 patients treated with SIVEXTRO were male (66%) and White (67%). Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation Serious adverse reactions occurred in 37/1425 (2.6%) of patients treated with SIVEXTRO and in 25/1000 (2.5%) of patients treated with the comparator. SIVEXTRO was discontinued due to an adverse reaction in 14/1425 (1%) of patients and the comparator was discontinued due to an adverse reaction in 13/1000 (1.3%) of patients. Most Common Adverse Reactions The most common adverse reactions in 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 2 lists selected adverse reactions occurring in at least 2% of patients treated with SIVEXTRO in clinical trials. Table 2: Selected Adverse Reactions Occurring in ≥2% of 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 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: Clostridium 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, VIIth 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 3. Table 3: Potentially Clinically Significant Lowest Laboratory Values in the Pooled Phase 3 ABSSSI Clinical Trials 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 × 103/mm3) (989) 2.1% (950) 3.8% Absolute neutrophil count (<0.8 × 103/mm3) (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 3). 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, 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). No data are available for patients exposed to SIVEXTRO for longer than 6 days.