Sivextro Drug Information

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 ) (<9 g/dL ) 3.4% 3.4% Platelet count (<112 × 10 3 /mm 3 ) 2.1% 3.8% Absolute neutrophil count (<0.8 × 10 3 /mm 3 ) 0.4% 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 ) (<9 g/dL ) 2.4% 0.0% Platelet count (<112 × 10 3 /mm 3 ) 1.2% 0.0% Absolute neutrophil count (<0.8 × 10 3 /mm 3 ) 0.0% 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.

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.

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

Membrane Transporters 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.

Serotonergic Agents

In postmarketing experience, there have been reports of serotonin syndrome in patients taking SIVEXTRO with serotonergic agents .

Pregnancy 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. (see Data ) 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 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).

Pediatric Use 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 . 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.

In the event of overdosage, SIVEXTRO should be discontinued and general supportive treatment given. Hemodialysis does not result in meaningful removal of tedizolid from systemic circulation.