This information is not for clinical use. These highlights do not include all the information needed to use Sivextro safely and effectively. Before taking Sivextro please consult with your doctor. See full prescribing information for Sivextro.

Indications And Usage

SIVEXTRO is an oxazolidinone-class antibacterial drug indicated in adults for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by designated susceptible bacteria. (1.1) 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 susceptible bacteria. 1.1 Acute Bacterial Skin and Skin Structure Infections SIVEXTRO® is an oxazolidinone-class antibacterial 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. 1.2 Usage 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 ABSSSI 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.

Does this card cost me anything?

NO - The Pharmacy Savings Card alone does not cost you anything

Dosage And Administration

Table 1: Dosage of SIVEXTRO
Infection Route Dosage Frequency Infusion Time Duration of Treatment
Acute Bacterial Skin and Skin Structure Infection (ABSSSI) Intravenous 200 mg Once daily 1 hour 6 days
Oral 200 mg Once daily Not Applicable

Dosage Forms And Strengths

SIVEXTRO 200 mg tablet is a yellow film-coated oval tablet; each tablet is debossed with "TZD" on one side and "200" on the other side. SIVEXTRO for injection is a sterile, white to off-white lyophilized powder for injection in single-use vials of 200 mg. Each 200 mg vial must be reconstituted with Sterile Water for Injection and subsequently diluted only with 0.9% Sodium Chloride Injection, USP. For injection: 200 mg, sterile, lyophilized powder in single-use vial for reconstitution for intravenous infusion; Tablet: 200 mg (3)

Contraindications

None None (4)

Warning and Cautions

Patients with neutropenia: The safety and efficacy of SIVEXTRO in patients with neutropenia (neutrophil counts <1000 cells/mm3) 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. (5.1) Clostridium difficile-associated diarrhea: Evaluate if diarrhea occurs. (5.2) 5.1 Patients with Neutropenia The safety and efficacy of SIVEXTRO in patients with neutropenia (neutrophil counts <1000 cells/mm3) 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 acute bacterial skin and skin structure infection. 5.2 Clostridium difficile-Associated Diarrhea Clostridium 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 antibiotic 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. 5.3 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.

Adverse Reactions

The most common adverse reactions (≥2%) are nausea, headache, diarrhea, 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 1050 patients treated with SIVEXTRO and 662 patients treated with the comparator antibacterial drug in two Phase 2 and two Phase 3 clinical trials. The median age of patients treated with SIVEXTRO in the Phase 2 and Phase 3 trials was 42 years, ranging between 17 and 86 years old. Patients treated with SIVEXTRO were predominantly male (65%) and White (82%). Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation Serious adverse reactions occurred in 12/662 (1.8%) of patients treated with SIVEXTRO and in 13/662 (2.0%) of patients treated with the comparator. SIVEXTRO was discontinued due to an adverse reaction in 3/662 (0.5%) of patients and the comparator was discontinued due to an adverse reaction in 6/662 (0.9%) of patients. Most Common Adverse Reactions The most common adverse reactions in patients treated with SIVEXTRO were nausea (8%), headache (6%), diarrhea (4%), vomiting (3%), and dizziness (2%). 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=662) Linezolid (600 mg oral/intravenous twice daily for 10 days) (N=662) Gastrointestinal Disorders Nausea 8% 12% Diarrhea 4% 5% Vomiting 3% 6% Nervous System Disorder Headache 6% 6% Dizziness 2% 2% Safety was additionally evaluated in a randomized, double-blind, multicenter study conducted in China, the Philippines, Taiwan, and the US, which included a total of 292 adult patients treated with tedizolid 200 mg administered IV and/or oral once daily for 6 days for the treatment of ABSSSI. The safety profile in this study was similar to the Phase 3 clinical trials; however, infusion site reactions (phlebitis) were reported in 3.1% of tedizolid-treated subjects, particularly among Asian patients. 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 General Disorders and Administration Site Conditions: infusion-related reactions Immune System Disorders: drug hypersensitivity Infections and Infestations: Clostridium difficile colitis, oral candidiasis, vulvovaginal mycotic infection Investigations: hepatic transaminases 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 values normal at baseline Represents lowest abnormal post-baseline value through the last dose of active drug SIVEXTRO (200 mg oral/intravenous once daily for 6 days) (N=618)Number of patients with non-missing laboratory values Linezolid (600 mg oral/intravenous twice daily for 10 days) (N=617) M = male; F = female Hemoglobin (<10.1 g/dL [M]) (<9 g/dL [F]) 3.1% 3.7% Platelet count (<112 × 103/mm3) 2.3% 4.9% Absolute neutrophil count (<0.8 × 103/mm3) 0.5% 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. 0.6% for tedizolid phosphate and linezolid, respectively; optic nerve disorders 0.3% vs. 0.2%, respectively). No data are available for patients exposed to SIVEXTRO for longer than 6 days.

Drug Interactions

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).] 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)

Use In Specific Populations

8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of SIVEXTRO in pregnant women. SIVEXTRO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In embryo-fetal studies, tedizolid phosphate was shown to produce fetal developmental toxicities in mice, rats, and rabbits. Fetal developmental effects occurring in mice in the absence of maternal toxicity included reduced fetal weights and an increased incidence of costal cartilage anomalies at the high dose of 25 mg/kg/day (4-fold the estimated human exposure level based on AUCs). In rats, decreased fetal weights and increased skeletal variations including reduced ossification of the sternebrae, vertebrae, and skull were observed at the high dose of 15 mg/kg/day (6-fold the estimated human exposure based on AUCs) and were associated with maternal toxicity (reduced maternal body weights). In rabbits, reduced fetal weights but no malformations or variations were observed at doses associated with maternal toxicity. The no observed adverse effect levels (NOAELs) for fetal toxicity in mice (5 mg/kg/day), maternal and fetal toxicity in rats (2.5 mg/kg/day), and rabbits (1 mg/kg/day) were associated with tedizolid plasma area under the curve (AUC) values approximately equivalent to (mice and rats) or 0.04-fold (rabbit) the tedizolid AUC value associated with the oral human therapeutic dose. In a pre-postnatal study, there were no adverse maternal or offspring effects when female rats were treated during pregnancy and lactation with tedizolid phosphate at the highest tested dose of 3.75 mg/kg/day, with plasma tedizolid exposure (AUC) approximately equivalent to the human plasma AUC exposure at the clinical dose of 200 mg/day. 8.3 Nursing Mothers Tedizolid is excreted in the breast milk of rats. It is not known whether tedizolid is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when SIVEXTRO is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness in pediatric patients below the age of 18 have not been established. 8.5 Geriatric Use Clinical studies of SIVEXTRO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. No overall differences in pharmacokinetics were observed between elderly subjects and younger subjects.