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 infections 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.

2.1 Important Administration Instructions for Pediatric Patients Weighing Less than 35 kg

Do not administer SIVEXTRO Tablets to pediatric patients weighing less than 35 kg [see Dosage and Administration 2.3].

2.2 Recommended Dosage for Adult Patients

The recommended dosage of SIVEXTRO is 200 mg administered once daily for six (6) days either as an oral tablet (with or without food) or as an intravenous (IV) infusion in adult patients.

The recommended dosage and administration of SIVEXTRO in adult patients are described in Table 1.

No dose adjustment is necessary when changing from intravenous to oral SIVEXTRO.

2.3 Recommended Dosage for Pediatric Patients

Recommended Dosage of SIVEXTRO for Injection for Pediatric Patients: Intravenous Dosage

The recommended intravenous dosage of SIVEXTRO for Injection for pediatric patients (at least 26 weeks gestational age and weighing at least 1 kg) is presented in Table 2.

Recommended Dosage of SIVEXTRO Tablets for Pediatric Patients: Oral Dosage

The recommended oral dosage of SIVEXTRO Tablets for pediatric patients is presented in Table 3. SIVEXTRO Tablets can be administered with or without food. Do not administer SIVEXTRO Tablets to pediatric patients weighing less than 35 kg.

No dose adjustment is necessary when changing from intravenous to oral SIVEXTRO.

2.4 Recommendations Regarding Missed Doses(s)

For Once Daily Oral Dosing of SIVEXTRO Tablets

If patients miss a dose, administer the dose as soon as possible anytime up to 8 hours prior to their next scheduled dose. If less than 8 hours remain before the next dose, instruct the patients to wait until their next scheduled dose.

2.5 Preparation and Administration of Intravenous Solution

SIVEXTRO is supplied as a sterile, lyophilized powder for injection in single-dose vials of 200 mg. Each 200 mg vial must be reconstituted with Sterile Water for Injection and subsequently diluted with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP.

SIVEXTRO vials contain no antimicrobial preservatives and are intended for single dose only. Discard any unused portion.

2.6 Compatible Intravenous Solutions

SIVEXTRO is compatible with 0.9% Sodium Chloride Injection, USP and 5% Dextrose Injection, USP.

Limited data are available on the compatibility of SIVEXTRO for Injection with other intravenous substances, additives or other medications and they should not be added to SIVEXTRO single-dose vials or infused simultaneously. If the same intravenous line is used for sequential infusion of several different drugs, the line should be flushed before and after infusion of SIVEXTRO with 0.9% Sodium Chloride Injection, USP.

2.7 Incompatibilities

SIVEXTRO for Injection is incompatible with any solution containing divalent cations (e.g., Ca2+, Mg2+), including Lactated Ringer’s Injection and Hartmann’s Solution.

5.1 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 [see Clinical Pharmacology (12.2)]. Alternative therapies should be considered when treating patients with neutropenia and ABSSSI.

5.2 Clostridioides difficile-Associated Diarrhea

Clostridioides difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents including SIVEXTRO, with severity ranging from mild diarrhea to fatal colitis. Treatment with antibacterial agents can alter the normal flora of the colon and may permit overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antibacterial therapy and may require colectomy. CDAD must be considered in 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. Appropriate measures such as fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

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.

6.1 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%).

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

8.1 Pregnancy

8.2 Lactation

8.4 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 [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.

8.5 Geriatric Use

Clinical studies of SIVEXTRO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. No overall differences in pharmacokinetics were observed between elderly subjects and younger subjects.

12.1 Mechanism of Action

Tedizolid is an antibacterial drug [see Microbiology (12.4)].

12.2 Pharmacodynamics

The AUC/minimum inhibitory concentration (MIC) was shown to best correlate with tedizolid activity in animal infection models.

In the mouse thigh infection model of S. aureus, antistaphylococcal killing activity was impacted by the presence of granulocytes. In granulocytopenic mice (neutrophil count <100 cells/mL), bacterial stasis was achieved at a human-equivalent dose of approximately 2000 mg/day; whereas, in non-granulocytopenic animals, stasis was achieved at a human-equivalent dose of approximately 100 mg/day. The safety and efficacy of SIVEXTRO for the treatment of neutropenic patients (neutrophil counts <1000 cells/mm3) have not been evaluated.

12.3 Pharmacokinetics

Tedizolid phosphate is a prodrug that is converted by phosphatases to tedizolid, the microbiologically active moiety, following oral and intravenous administration. Only the pharmacokinetic profile of tedizolid is discussed further due to negligible systemic exposure of tedizolid phosphate following oral and intravenous administration. Following multiple once-daily oral or intravenous administration, steady-state concentrations are achieved within approximately three days with tedizolid accumulation of approximately 30% (tedizolid half-life of approximately 12 hours). Pharmacokinetic (PK) parameters of tedizolid following oral and intravenous administration of 200 mg once daily tedizolid phosphate in adults are shown in Table 8.

12.4 Microbiology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

Repeated-oral and intravenous dosing of tedizolid phosphate in rats in 1 month and 3 month toxicology studies produced dose- and time-dependent bone marrow hypocellularity (myeloid, erythroid, and megakaryocyte), with associated reduction in circulating RBCs, WBCs, and platelets. These effects showed evidence of reversibility and occurred at plasma tedizolid exposure levels (AUC) ≥6-fold greater than the plasma exposure associated with the human therapeutic dose. In a 1-month immunotoxicology study in rats, repeated oral dosing of tedizolid phosphate was shown to significantly reduce splenic B cells and T cells and reduce plasma IgG titers. These effects occurred at plasma tedizolid exposure levels (AUC) ≥3-fold greater than the expected human plasma exposure associated with the therapeutic dose.

14.1 Acute Bacterial Skin and Skin Structure Infections

Adults

A total of 1333 adults with acute bacterial skin and skin structure infections (ABSSSI) were randomized in two multicenter, multinational, double-blind, non-inferiority trials. Both trials compared SIVEXTRO 200 mg once daily for 6 days versus linezolid 600 mg every 12 hours for 10 days. In Trial 1, patients were treated with oral therapy, while in Trial 2, patients could receive oral therapy after a minimum of one day of intravenous therapy. Patients with cellulitis/erysipelas, major cutaneous abscess, or wound infection were enrolled in the trials. Patients with wound infections could have received aztreonam and/or metronidazole as adjunctive therapy for gram-negative bacterial coverage, if needed. The intent-to-treat (ITT) patient population included all randomized patients.

In Trial 1, 332 patients with ABSSSI were randomized to SIVEXTRO and 335 patients were randomized to linezolid. The majority (91%) of patients treated with SIVEXTRO in Trial 1 were less than 65 years old with a median age of 43 years (range: 18 to 86 years). Patients treated with SIVEXTRO were predominantly male (61%) and White (84%); 13% had BMI ≥35 kg/m2, 8% had diabetes mellitus, 35% were current or recent intravenous drug users, and 2% had moderate to severe renal impairment. The overall median surface area of infection was 188 cm2. The types of ABSSSI included were cellulitis/erysipelas (41%), wound infection (29%), and major cutaneous abscess (30%). In addition to local signs and symptoms of infection, patients were also required to have at least one regional or systemic sign of infection at baseline, defined as lymphadenopathy (87% of patients), temperature 38°C or higher (16% of patients), white blood cell count greater than 10,000 cells/mm3 or less than 4000 cells/mm3 (42%), or 10% or more band forms on white blood cell differential (4%).

The primary endpoint in Trial 1 was early clinical response defined as no increase from baseline lesion area at 48-72 hours after the first dose and oral temperature of ≤37.6°C, confirmed by a second temperature measurement within 24 hours in the ITT population.

In Trial 2, 332 patients with ABSSSI were randomized to SIVEXTRO and 334 patients were randomized to linezolid. The majority (87%) of patients treated with SIVEXTRO in Trial 2 were less than 65 years old with a median age of 46 years (range: 17 to 86 years). Patients treated with SIVEXTRO were predominantly male (68%) and White (86%); 16% had BMI ≥35 kg/m2, 10% had diabetes mellitus, 20% were current or recent intravenous drug users, and 4% had moderate to severe renal impairment. The overall median surface area of infection was 231 cm2. The types of ABSSSI included were cellulitis/erysipelas (50%), wound infection (30%), and major cutaneous abscess (20%). In addition to local signs and symptoms of infection, patients were also required to have at least one regional or systemic sign of infection at baseline, defined as lymphadenopathy (71% of patients), temperature 38°C or higher (31% of patients), white blood cell count greater than 10,000 cells/mm3 or less than 4000 cells/mm3 (53%), or 10% or more band forms on white blood cell differential (16%).

The primary endpoint in Trial 2 was early clinical response defined as at least a 20% decrease from baseline lesion area at 48-72 hours after the first dose in the ITT population (Table 10).

An investigator assessment of clinical response was made at the post-therapy evaluation (PTE) (7 - 14 days after the end of therapy) in the ITT and CE (Clinically Evaluable) populations. Clinical success was defined as resolution or near resolution of most disease-specific signs and symptoms, absence or near resolution of systemic signs of infection if present at baseline (lymphadenopathy, fever, >10% immature neutrophils, abnormal WBC count), and no new signs, symptoms, or complications attributable to the ABSSSI requiring further treatment of the primary lesion (Table 11).

Clinical success by baseline pathogens from the primary infection site or blood cultures for the microbiological intent-to-treat (MITT) patient population for two integrated Phase 3 ABSSSI studies are presented in Table 12 and Table 13.

Baseline bacteremia in the tedizolid arm with relevant pathogens included two subjects with MRSA, four subjects with MSSA, two subjects with S. pyogenes, one subject with S. agalactiae, and one subject with S. constellatus. All of these subjects were Responders at the 48-72 hour evaluation. At the Post-therapy Evaluation (PTE), 8 of 10 subjects were considered clinical successes.

Baseline bacteremia in the tedizolid arm with relevant pathogens included two subjects with MRSA, four subjects with MSSA, two subjects with S. pyogenes, one subject with S. agalactiae, and one subject with S. constellatus. All of these subjects were Responders at the 48-72 hour evaluation. At the Post-therapy Evaluation (PTE) 8 of 10 subjects were considered clinical successes.

Pediatric Patients

The safety and efficacy of SIVEXTRO were investigated in Pediatric Trials 1 and 2. Pediatric Trial 1 included pediatric patients 12 to < 18 years of age who were investigated in a randomized, single blind, active-controlled trial of 120 patients with clinically documented ABSSSI (91 receiving tedizolid, 29 receiving comparator). Patients were randomized in a 3:1 ratio with stratification by geographic region to receive SIVEXTRO IV and/or oral therapy, dosed 200 mg once daily for 6 days, or comparator IV and/or oral therapy, dosed over 10 days. Comparator therapy was selected by the investigator from a list of 5 IV and 4 oral comparators per local standard of care. The most frequently used comparators were cefazolin (11 patients) and vancomycin (8 patients).

Additionally, Pediatric Trial 2 (NCT03176134) evaluated the safety and efficacy of SIVEXTRO in pediatric patients 4 months to <12 years of age in a randomized, single blind, active-controlled trial of 100 patients with clinically documented ABSSSI (75 receiving tedizolid, 25 receiving comparator). Patients were randomized in a 3:1 ratio to receive SIVEXTRO for 6 to 10 days or comparator for 10 to 14 days. SIVEXTRO (IV and/or oral) was dosed as a weight-based dose of 2 to 2.5 mg/kg every 12 hours or as 200 mg given once daily. Patients who received oral therapy received an oral suspension formulation that is not currently approved for use. Comparator therapy was selected from a pre-specified list by the investigator and dosed per local standard of care.

The primary objective of Pediatric Trials 1 and 2 was to evaluate the safety and tolerability of SIVEXTRO. The trials were not powered for comparative inferential efficacy analysis. Clinical response at the test of cure visit (Day 18-25) was assessed by a blinded investigator in the ITT population (all randomized patients). Clinical successes were required to have resolution or near resolution of all related signs and symptoms such that no further antibacterial therapy was needed. Early clinical response, defined as at least a 20% reduction in lesion size at 48-72 hours after start of treatment, was also assessed in the ITT population.

In Pediatric Trial 1, clinical success at test of cure was 96.7% (88/91) in the tedizolid group and 93.1% (27/29) in the comparator group (difference: 3.6%, 95% CI: -6.3, 13.5). Early clinical response at 48-72 hours was 92.3% (84/91) in the tedizolid group and 96.6% (28/29) in the comparator group (difference: -4.2%, 95% CI: -12.9, 4.4).

In Pediatric Trial 2, clinical success at test of cure was 93.3% (70/75) in the tedizolid group and 92.0% (23/25) in the comparator group (difference: 1.3%, 95% CI: -10.7, 13.4). Early clinical response was not adequately assessed in Pediatric Trial 2 because an in-person outpatient visit at this timepoint was not required during the COVID-19 pandemic.

16.1 Tablets

SIVEXTRO Tablets are yellow film-coated oval tablets containing 200 mg of tedizolid phosphate; each tablet is debossed with "TZD" on one side and "200" on the other side.

They are supplied as follows:

HDPE bottles of 30 tablets with child-resistant closure (NDC 67919-041-04)

Unit dose blister packs of 6 tablets (NDC 67919-041-05)

16.2 For Injection

SIVEXTRO is supplied as a sterile, white to off-white lyophilized powder for injection in single-dose vials of 200 mg. Each 200 mg vial must be reconstituted with Sterile Water for Injection and subsequently diluted with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP.

They are supplied as follows:

Package of ten 200 mg single-dose vials (NDC 67919-040-02)

16.3 Storage and Handling

SIVEXTRO Tablets and SIVEXTRO for Injection should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Discard any unused portion of the single-dose vials.

Administration with Food

Patients should be informed that SIVEXTRO Tablets may be taken with or without food and without any dietary restrictions [see Dosage and Administration (2.2, 2.3) and Clinical Pharmacology (12.3)].

Antibacterial Resistance

Patients should be counseled that antibacterial drugs including SIVEXTRO should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When SIVEXTRO is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by SIVEXTRO or other antibacterial drugs in the future [see Indications and Usage (1.2)].

Missed Doses

Patients should be informed that if they miss a SIVEXTRO oral dose, they should take the dose as soon as possible anytime up to 8 hours prior to their next scheduled dose. If less than 8 hours remains before the next dose, then they should wait until their next scheduled dose. Patients should take the prescribed number of doses [see Dosage and Administration (2.2, 2.3)].

Potentially Serious Adverse Reactions

Patients should be advised that diarrhea is a common problem caused by antibacterial drugs including SIVEXTRO and usually resolves when the drug is discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop frequent watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial drug and may be a sign of a more serious intestinal infection [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)]. If this occurs, patients should contact their healthcare provider as soon as possible.

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 [see Use in Specific Populations (8.1)].