Drug Safety-related Labeling Changes (SrLC)

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SIVEXTRO (NDA-205435)

(TEDIZOLID PHOSPHATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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02/27/2026 (SUPPL-19)

Approved Drug Label (PDF)

5 Warnings and Precautions

 

5.1 Serotonin Syndrome

Newly added section:

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.

6 Adverse Reactions

Additions and/or revisions undelined:

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)]

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Nervous system disorders: serotonin syndrome

7 Drug Interactions

7.1 Membrane Transporters

Newly added subsection title

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

Newly added subsection

In post marketing 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)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Serotonin Syndrome

Advise patients to inform their healthcare provider if they are taking serotonergic agents and of the increased risk of serotonin syndrome when SIVEXTRO is used concomitantly with serotonergic agents [see Warnings and Precautions (5.1)].

PATIENT INFORMATION

Additions and/or revisions underlined:

…

SIVEXTRO tablet is not for use in children weighing less than 77 pounds (35 kg).

…

Are you taking other medicines?

…

• It is especially important to tell your healthcare provider if you take any of the following medicines:

• Methotrexate (for cancer or rheumatoid arthritis)

• Topotecan (for cancer)

• Rosuvastatin (for cholesterol)

• Depression or anxiety medicines

• Migraine headache medicines called triptans

• Prescription pain medicines

…

What are the possible side effects of SIVEXTRO?

SIVEXTRO may cause serious side effects, including

• Serotonin syndrome. Taking SIVEXTRO with certain other medicines can cause a potentially life-threatening problem called serotonin syndrome. See “Are you taking other medicines?” Call your healthcare provider or go to the nearest hospital emergency room right away if you have any of the following signs or symptoms of serotonin syndrome:

  • high body temperature (hyperthermia)

  • sweating too much

  • agitation

  • difficulty with coordination

  • stiff muscles or muscle twitching

  • unusual eye movement

  • tremors

  • fever

…

04/04/2025 (SUPPL-16)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

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%).

…

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 × 103/mm3.

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 greater than or equal to 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.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of SIVEXTRO for the treatment of ABSSSI have been established in pediatric patients at least 26 weeks gestational age and weighing at least 1 kg. 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 from birth (includes neonates at least 26 weeks gestational age) to less than 18 years of age [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)].

The safety and effectiveness of SIVEXTRO in pediatric patients less than 26 weeks gestational age and weighing less than 1 kg have not been established.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

Additions and/or revisions, please refer to label for complete information.

11/17/2021 (SUPPL-14)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined: 

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). 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.

6.2 Postmarketing Experience

Newly added subsection: 

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

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Patient Information

Newly added section; please refer to label 

06/19/2020 (SUPPL-12)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Clostridioides difficile-Associated Diarrhea

(“Clostridium” replaced with “Clostridioides”)

6 Adverse Reactions

(Extensive changes; please refer to label)

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions underlined)

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 [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)].

Safety and effectiveness of SIVEXTRO in pediatric patients below the age of 12 years have not been established.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Patient Information

(Newly added section; please refer to label)

09/09/2019 (SUPPL-11)

Approved Drug Label (PDF)

8 Use in Specific Populations

Lactation Risk Summary

Newly added information:

There is no information on the presence of tedizolid in human milk. Tedizolid is present in rat milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. There are no data on the effects of SIVEXTRO on the breastfed child or on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SIVEXTRO and any potential adverse effects on the breastfed child from SIVEXTRO or from the underlying maternal condition.

Pregnancy

Newly added information:

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.

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).

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Newly added information:

Embryo-Fetal Toxicity

Based on animal data, advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy.

03/06/2019 (SUPPL-10)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Adverse Reactions in Clinical Trials

(subsection revised, additions and revisions underline)

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.

 

(please refer to Table 2 in label)

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.

 

The following selected adverse reactions were reported in SIVEXTRO-treated patients at a rate of less than 2% in these clinical trials:

…

 

Investigations: hepatic transaminases increased (ALT increased, AST increased), gamma-glutamyltransferase (GGT) increased, white blood cell count decreased

 

…

 

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.

(please refer to Table 3 in label)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

(additions underlined)

…

Problems with your vascular system

• high blood pressure

   

  Problems with your blood work

  Your doctor may tell you that you have the following while taking Sivextro:

• a low white blood cell count

• anemia (low red blood cells)

• bleeding or bruising easily

• increased levels of liver enzymes

   

  …

08/12/2017 (SUPPL-7)

Approved Drug Label (PDF)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Patient Information

(Newly added subsection; please refer to label)

08/12/2017 (SUPPL-8)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Adverse Reactions in Clinical Trials

(Additions and/or revisions are underlined)

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.

10/28/2016 (SUPPL-3)

Approved Drug Label (PDF)

7 Drug Interactions

(addition underlined)

 

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.