Preparation

The contents of the vial should be reconstituted using aseptic technique as follows:

Note: To minimize foaming, AVOID vigorous agitation or shaking of the vial during or after reconstitution. 

1. Reconstitute the SIVEXTRO vial with 4 mL of Sterile Water for Injection.
2. Gently swirl the contents and let the vial stand until the cake has completely dissolved and any foam disperses.
3. Inspect the vial to ensure the solution contains no particulate matter and no cake or powder remains attached to the sides of the vial.  If necessary, invert the vial to dissolve any remaining powder and swirl gently to prevent foaming.  The reconstituted solution is clear and colorless to pale-yellow in color; the total storage time should not exceed 24 hours at either room temperature or under refrigeration at 2°C to 8°C (36°F to 46°F).
4. Tilt the upright vial and insert a syringe with appropriately sized needle into the bottom corner of the vial and remove 4 mL of the reconstituted solution.  Do not invert the vial during extraction.
5. The reconstituted solution must be further diluted in 250 mL of 0.9% Sodium Chloride Injection, USP.  Slowly inject the 4 mL of reconstituted solution into a 250 mL bag of 0.9% Sodium Chloride Injection, USP.  Invert the bag gently to mix.  Do NOT shake the bag as this may cause foaming.

Administration

Administer as an intravenous infusion only.  

Do not administer as an intravenous push or bolus.  Do not mix SIVEXTRO with other drugs when administering.  It is not intended for intra-arterial, intramuscular, intrathecal, intraperitoneal, or subcutaneous administration. 

The intravenous bag containing the reconstituted and diluted intravenous solution should be inspected visually for particulate matter prior to administration.  Discard if visible particles are observed.  The resulting solution is clear and colorless to pale-yellow in color. 

After reconstitution and dilution, SIVEXTRO is to be administered via intravenous infusion using a total time of 1 hour.  

The total time from reconstitution to administration should not exceed 24 hours at room temperature or under refrigeration at 2°C to 8°C (36°F to 46°F). 

2.3 Compatible Intravenous Solutions

Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation

Serious adverse reactions occurred in 12/662 (1.8%) of patients treated with SIVEXTRO and in 13/662 (2.0%) of patients treated with the comparator.  SIVEXTRO was discontinued due to an adverse reaction in 3/662 (0.5%) of patients and the comparator was discontinued due to an adverse reaction in 6/662 (0.9%) of patients. 

Most Common Adverse Reactions

The most common adverse reactions in patients treated with SIVEXTRO were nausea (8%), headache (6%), diarrhea (4%), vomiting (3%), and dizziness (2%).  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. 

The following selected adverse reactions were reported in SIVEXTRO-treated 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

General Disorders and Administration Site Conditions: infusion-related reactions

Immune System Disorders: drug hypersensitivity

Infections and Infestations: Clostridium difficile colitis, oral candidiasis, vulvovaginal mycotic infection

Investigations: hepatic transaminases 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. 

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, reported adverse reactions for peripheral neuropathy and optic nerve disorders were similar between both treatment arms (peripheral neuropathy 1.2% vs.  0.6% for tedizolid phosphate and linezolid, respectively; optic nerve disorders 0.3% vs. 0.2%, respectively).  No data are available for patients exposed to SIVEXTRO for longer than 6 days.  

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of SIVEXTRO in pregnant women.  SIVEXTRO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 

In embryo-fetal studies, tedizolid phosphate was shown to produce fetal developmental toxicities in mice, rats, and rabbits.  Fetal developmental effects occurring in mice in the absence of maternal toxicity included reduced fetal weights and an increased incidence of costal cartilage anomalies at the high dose of 25 mg/kg/day (4-fold the estimated human exposure level based on AUCs).  In rats, decreased fetal weights and increased skeletal variations including reduced ossification of the sternabrae, vertebrae, and skull were observed at the high dose of 15 mg/kg/day (6-fold the estimated human exposure based on AUCs) and were associated with maternal toxicity (reduced maternal body weights).  In rabbits, reduced fetal weights but no malformations or variations were observed at doses associated with maternal toxicity.  The no observed adverse effect levels (NOAELs) for fetal toxicity in mice (5 mg/kg/day), maternal and fetal toxicity in rats (2.5 mg/kg/day), and rabbits (1 mg/kg/day) were associated with tedizolid plasma area under the curve (AUC) values approximately equivalent to (mice and rats) or 0.04-fold (rabbit) the tedizolid AUC value associated with the oral human therapeutic dose. 

In a pre-postnatal study, there were no adverse maternal or offspring effects when female rats were treated during pregnancy and lactation with tedizolid phosphate at the highest tested dose of 3.75 mg/kg/day, with plasma tedizolid exposure (AUC) approximately equivalent to the human plasma AUC exposure at the clinical dose of 200 mg/day. 

8.3 Nursing Mothers

Cardiac Electrophysiology

In a randomized, positive- and placebo-controlled crossover thorough QTc study, 48 enrolled subjects were administered a single oral dose of SIVEXTRO at a therapeutic dose of 200 mg, SIVEXTRO at a supratherapeutic dose of 1200 mg, placebo, and a positive control; no significant effects of SIVEXTRO on heart rate, electrocardiogram morphology, PR, QRS, or QT interval were detected.  Therefore, SIVEXTRO does not affect cardiac repolarization. 

12.3 Pharmacokinetics

Absorption

Peak plasma tedizolid concentrations are achieved within approximately 3 hours following oral administration under fasting conditions or at the end of the 1 hour intravenous infusion of tedizolid phosphate.  The absolute bioavailability is approximately 91% and no dosage adjustment is necessary between intravenous and oral administration. 

Tedizolid phosphate (oral) may be administered with or without food as total systemic exposure (AUC0-∞) is unchanged between fasted and fed (high-fat, high-calorie) conditions.  

Distribution

Protein binding of tedizolid to human plasma proteins is approximately 70 to 90%.  The mean steady state volume of distribution of tedizolid in healthy adults following a single intravenous dose of tedizolid phosphate 200 mg ranged from 67 to 80 L (approximately twice total body water).  Tedizolid penetrates into the interstitial space fluid of adipose and skeletal muscle tissue with exposure similar to free drug exposure in plasma. 

Metabolism

Other than tedizolid, which accounts for approximately 95% of the total radiocarbon AUC in plasma, there are no other significant circulating metabolites in humans. 

There was no degradation of tedizolid in human liver microsomes indicating tedizolid is unlikely to be a substrate for hepatic CYP450 enzymes. 

Excretion

Following single oral administration of 14C-labeled tedizolid phosphate under fasted conditions, the majority of elimination occurred via the liver, with 82% of the radioactive dose recovered in feces and 18% in urine, primarily as a non-circulating and microbiologically inactive sulfate conjugate.  Most of the elimination of tedizolid (>85%) occurs within 96 hours.  Less than 3% of the tedizolid phosphate-administered dose is excreted in feces and urine as unchanged tedizolid. 

Specific Populations

Based on the population pharmacokinetic analysis, there are no clinically relevant demographic or clinical patient factors (including age, gender, race, ethnicity, weight, body mass index, and measures of renal or liver function) that impact the pharmacokinetics of tedizolid. 

Drug Interaction Studies

Mechanism of Action

The antibacterial activity of tedizolid is mediated by binding to the 50S subunit of the bacterial ribosome resulting in inhibition of protein synthesis.  Tedizolid inhibits bacterial protein synthesis through a mechanism of action different from that of other non-oxazolidinone class antibacterial drugs; therefore, cross-resistance between tedizolid and other classes of antibacterial drugs is unlikely.  The results of in vitro time-kill studies show that tedizolid is bacteriostatic against enterococci, staphylococci, and streptococci. 

Mechanism of Resistance

Organisms resistant to oxazolidinones via mutations in chromosomal genes encoding 23S rRNA or ribosomal proteins (L3 and L4) are generally cross-resistant to tedizolid.  In the limited number of Staphylococcus aureus strains tested, the presence of the chloramphenicol-florfenicol resistance (cfr) gene did not result in resistance to tedizolid in the absence of chromosomal mutations. 

Frequency of Resistance

Spontaneous mutations conferring reduced susceptibility to tedizolid occur in vitro at a frequency rate of approximately 10-10. 

Interaction with Other Antimicrobial Drugs

In vitro drug combination studies with tedizolid and aztreonam, ceftriaxone, ceftazidime, imipenem, rifampin, trimethoprim/sulfamethoxazole, minocycline, clindamycin, ciprofloxacin, daptomycin, vancomycin, gentamicin, amphotericin B, ketoconazole, and terbinafine demonstrate neither synergy nor antagonism. 

Spectrum of Activity

Tedizolid has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections, as described in Indications and Usage (1). 

Staphylococcus aureus (including methicillin-resistant [MRSA] and methicillin-susceptible [MSSA] isolates)

 

Streptococcus pyogenes

 

Streptococcus agalactiae

 

Streptococcus anginosus Group (including S. anginosus, S. intermedius, and S. constellatus)

 

Enterococcus faecalis

Staphylococcus epidermidis (including methicillin-susceptible and methicillin-resistant isolates)

 

Staphylococcus haemolyticus

 

Staphylococcus lugdunensis

 

Enterococcus faecium

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide cumulative results of the in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens.  These reports should aid the physician in selecting an effective antibacterial drug for treatment. 

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs).  These MIC values provide estimates of the susceptibility of bacteria to antimicrobial compounds.  The MIC values should be determined using a standardized procedure based on dilution methods (broth, agar, or microdilution) or equivalent using standardized inoculum and concentrations of tedizolid.1, 3 The MIC values should be interpreted according to the criteria provided in Table 5. 

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds.  The standardized procedure requires the use of standardized inoculum concentrations.2, 3 This procedure uses paper disks impregnated with 20 mcg tedizolid to test the susceptibility of microorganisms to tedizolid.  Reports from the laboratory providing results of the standard single-disk susceptibility test with a 20 mcg tedizolid disk should be interpreted according to the criteria in Table 5. 

A report of "Susceptible" indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection.  A report of "Intermediate" indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative drugs, the test should be repeated.  This category implies possible clinical efficacy in body sites where the drug is physiologically concentrated.  This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation.  A report of "Resistant" indicates that the antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentrations usually achievable at the infection site; other therapy should be selected.