SIVEXTRO®

(tedizolid phosphate) 200 mg injection, for intravenous use; 200 mg tablet, for oral use

Safety

Adverse reactions in adult patients

The most common adverse reactions (≥2%) in adults for SIVEXTRO are nausea (7%), headache (5%), diarrhea (4%), vomiting (3%), and dizziness (2%).

In adult patients receiving SIVEXTRO intravenously, infusion- or injection-related adverse reactions including but not limited to: phlebitis, injection- or infusion-site pain or swelling, injection-site reaction, erythema, or induration, and infusion-related reaction occurred (4%).

The most common adverse reactions (>2%) in pediatric patients 12 years of age and older are phlebitis (3%) and increased hepatic transaminases (3%).

Selected adverse reactions occurring in ≥2% of adult patients in Phase 3 ABSSSI clinical trials

SIVEXTRO (N = 1037) Linezolid (N = 1000)
Gastrointestinal disorders
Nausea 7% 10%
Diarrhea 4% 5%
Vomiting 3% 5%
Nervous system disorders
Headache 5% 5%
Dizziness 2% 2%
Infusion- or injection-related adverse reactionsa
4% 2%

(a) 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.

Discontinuation rates

1% of adult patients receiving SIVEXTRO and 1.3% receiving linezolid discontinued treatment due to adverse reactions.

Hematological abnormalities

Incidence of hematological abnormalities in phase 3 ABSSSI clinical trials in adults 

Potentially clinically significant valuesb,c
Laboratory assay SIVEXTRO (200 mg oral/intravenous once daily for 6 days) (N)d Linezolid (600 mg oral/intravenous twice daily for 10 days) (N)d
Hemoglobin (<9 g/dL females; <10.1 g/dL males) (994) 3.4% (957) 3.4%
Platelet count (<112 x 103/mm3) (989) 2.1% (950) 3.8%
Absolute neutrophil count (<0.8 x 103/mm3) (980) 0.4% (941) 0.6%

(b) <75% (<50% for absolute neutrophil count) of lower limit of normal (LLN) for post-baseline measurements.

(c) Represents laboratory values within two days after the last dose of active drug.

(d) Number of subjects with at least one post-baseline test result that are within two days after the last dose of active drug.

The safety and effectiveness of SIVEXTRO for the treatment of ABSSSI have been established in pediatric patients aged 12 years and older. Use of SIVEXTRO for the treatment of ABSSSI is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients aged 12 years and older. Safety and effectiveness of SIVEXTRO in pediatric patients below the age of 12 years have not been established.

Adverse reactions in pediatric patients

Adverse reactions were evaluated in 91 pediatric patients with ABSSSI ranging from 12 to <18 years of age treated with IV and/or oral SIVEXTRO 200 mg for 6 days and 29 patients treated with comparator agents 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 pediatric patients receiving SIVEXTRO in the ABSSSI clinical trial were phlebitis (3%), increased hepatic transaminases (alanine aminotransferase, aspartate aminotransferase), (3%), anemia, and vomiting (1%).

Safety has not been evaluated in pediatric patients under 12 years of age.

Potentially clinically significant lowest laboratory values in the ABSSSI clinical trial in pediatric patients (12-<18 years)

Potentially clinically significant values *,†
Laboratory assay SIVEXTRO (200 mg oral/intravenous once daily for 6 days) (N) Comparators§ (for 10 days)(N)
Hemoglobin (<10.1 g/dL [M] <9 g/dL [F]) (85) 2.4% (26) 0.0%
Platelet count (<112 x 103/mm3) (82) 1.2% (26) 0.0%
Absolute neutrophil count (<0.8 x 103/mm3) (85) 0.0% (26) 0.0%

M, male; F, female

* <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

Number of subjects with at least one post-baseline test result that are within two days after the last dose of active drug

§ 5 IV and 4 oral comparators selected per local standard of care

Drug-drug interactions

Increased Breast Cancer Resistance Protein (BCRP) substrate plasma concentrations

SIVEXTRO, when administered orally, can increase the plasma concentrations of orally administered BCRP substrates. If possible, an interruption in the treatment of the co-administered BCRP substrates should be considered, especially for BCRP substrates with a narrow therapeutic index (eg methotrexate or topotecan). If coadministration cannot be avoided, monitor for adverse reactions related to the concomitantly administered BCRP substrates, including rosuvastatin.

No known interactions with serotonergic agents

Serotonergic effects at doses of tedizolid phosphate up to 30-fold above the human equivalent dose did not differ from vehicle control in a mouse model that predicts serotonergic activity.

In phase 3 trials, subjects taking serotonergic agents including antidepressants were excluded.

No known interactions with adrenergic agents

2 placebo-controlled crossover studies with SIVEXTRO (at steady state) showed no meaningful changes in blood pressure or heart rate with pseudoephedrine, and the median tyramine dose required to cause an increase in systolic blood pressure (≥30 mmHg) was 325 mg with SIVEXTRO compared to 425 mg with placebo.

Palpitations were reported in 21/29 (72.4%) subjects exposed to SIVEXTRO in the tyramine challenge study vs 13/28 (46.4%) of placebo patients.

Monoamine oxidase inhibitors

Tedizolid is a reversible inhibitor of monoamine oxidase (MAO) in vitro. The interaction with MAO inhibitors could not be evaluated in phase 2 and 3 trials, as subjects taking such medications were excluded from the trials.

Indication

SIVEXTRO is an oxazolidinone-class antibacterial indicated in adults and pediatric patients 12 years of age and older 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.

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.

Selected Safety Information

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. Alternative therapies should be considered when treating patients with neutropenia.

Clostridioides difficile–associated diarrhea (CDAD), ranging from mild diarrhea to fatal colitis, has been reported with nearly all systemic antibacterial agents, including SIVEXTRO. Evaluate 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.

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%) in adults for SIVEXTRO are nausea (7%), headache (5%), diarrhea (4%), vomiting (3%), and dizziness (2%). 

In adult patients receiving SIVEXTRO intravenously, infusion- or injection-related adverse reactions including but not limited to: phlebitis, injection- or infusion-site pain or swelling, injection-site reaction, erythema, or induration, and infusion-related reaction occurred (4%). 

The most common adverse reactions (>2%) in pediatric patients 12 years of age and older are phlebitis (3%) and increased hepatic transaminases (3%).

Drug interactions with BCRP substrates: SIVEXTRO (when administered orally) can increase the plasma concentrations of orally administered Breast Cancer Resistance Protein (BCRP) substrates and the potential for adverse reactions. Monitor for adverse reactions related to the concomitant BCRP substrates if coadministration cannot be avoided.

Before prescribing SIVEXTRO, please read the accompanying Prescribing Information. The Patient Information also is available.

US-SIV-0044710/20