SIVEXTRO
Generic: TEDIZOLID PHOSPHATE
Basic Information
Manufacturer
Merck Sharp & Dohme LLC
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
INTRAVENOUS
FDA Set ID
75672079-589f-451a-bdbf-eaebcfcc80a9
Indications & Usage
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.
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.
Adverse Reactions
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
( 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