SIVEXTRO (Page 2 of 7)

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.

6 ADVERSE REACTIONS

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.

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 2 lists selected adverse reactions occurring in at least 2% of adult patients treated with SIVEXTRO in clinical trials.

Table 2: 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)
*
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.
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 *
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, 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 in Adults
Laboratory Assay Potentially Clinically Significant Values *,
SIVEXTRO(200 mg oral/intravenous once daily for 6 days)(N) Linezolid(600 mg oral/intravenous twice daily for 10 days)(N)
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
Hemoglobin (<10.1 g/dL [M]) (<9 g/dL [F]) (994)3.4% (957)3.4%
Platelet count (<112 × 103 /mm3) (989)2.1% (950)3.8%
Absolute neutrophil count (<0.8 × 103 /mm3) (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 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 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).

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.

Laboratory Parameters

Table 4: Potentially Clinically Significant Lowest Laboratory Values in the ABSSSI Clinical Trial in Pediatric Patients (12-<18 years)
Laboratory Assay Potentially Clinically Significant Values *,
SIVEXTRO(200 mg oral/intravenousonce daily for 6 days) (N) Comparators §(for 10 days)(N)
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
Hemoglobin (<10.1 g/dL [M]) (<9 g/dL [F]) (85)2.4% (26)0.0%
Platelet count (<112 × 103 /mm3) (82)1.2% (26)0.0%
Absolute neutrophil count (<0.8 × 103 /mm3) (85)0.0% (26)0.0%

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