Sivextro

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

• Sivextro^®

Unless your doctor tells you otherwise, continue your normal diet.

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Sivextro is part of the drug class:

• OTHER ANTIBACTERIALS

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if Sivextro crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using Sivextro.

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The recommended dose of tedizolid (Sivextro) is 200 mg administered once daily for six (6) days.

If you take too much Sivextro, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

If Sivextro is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

Antibacterial; oxazolidinone.1 5 6 10

Tedizolid phosphate and tedizolid not substrates for and do not inhibit or induce CYP isoenzymes (CYP1A2, 2B6, 2D6, 2C8, 2C9, 2C19, 3A4) in vitro.1 21 Drug interactions involving oxidative metabolism and CYP isoenzymes unlikely.1

No clinically important effect on drug uptake or drug efflux membrane transporters (e.g., organic anion transporter [OAT] 1, OAT3, organic anion transporting polypeptide [OATP] 1B1, OATP1B3, organic cation transporter [OCT] 1, OCT2, P-glycoprotein [P-gp], breast cancer resistance protein [BCRP]) in vitro.1

Specific Drugs and Foods

None

Sivextro (tedizolid phosphate), a phosphate prodrug, is converted to tedizolid in the presence of phosphatases.

Tedizolid phosphate has the chemical name [(5R)-(3-{3-Fluoro-4-[6-(2-methyl-2H-tetrazol- 5-yl) pyridin-3-yl]phenyl}-2-oxooxazolidin- 5-yl]methyl hydrogen phosphate.

Its empirical formula is C17H16FN6O6P and its molecular weight is 450.32. Its structural formula is:

Tedizolid phosphate is a white to yellow solid and is administered orally or by intravenous infusion.

The pharmacologically active moiety, tedizolid, is an antibacterial agent of the oxazolidinone class.

Sivextro tablets contain 200 mg of tedizolid phosphate, and the following inactive ingredients: microcrystalline cellulose, mannitol, crospovidone, povidone, and magnesium stearate. In addition, the film coating contains the following inactive ingredients: polyvinyl alcohol, titanium dioxide, polyethylene glycol/macrogol, talc, and yellow iron oxide.

Sivextro for injection is a sterile, white to off-white sterile lyophilized powder for injection in single-use vials of 200 mg. The inactive ingredients are mannitol (105 mg), sodium hydroxide, and hydrochloric acid, which is used in minimal quantities for pH adjustment.

Mechanism of Action

Tedizolid phosphate is the prodrug of tedizolid, an antibacterial agent [see Clinical Pharmacology (12.3), (12.4)].

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.

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.

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 are shown in Table 4.

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.

In vitro studies showed that conjugation of tedizolid is mediated via multiple sulfotransferase (SULT) isoforms (SULT1A1, SULT1A2, and SULT2A1).

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.

Hepatic Impairment

Following administration of a single 200 mg oral dose of Sivextro, no clinically meaningful changes in mean tedizolid Cmax and AUC0-∞ were observed in patients with moderate (n=8) or severe (n=8) hepatic impairment (Child-Pugh Class B and C) compared to 8 matched healthy control subjects. No dose adjustment is necessary for patients with hepatic impairment.

Renal Impairment

Following administration of a single 200 mg intravenous dose of Sivextro to 8 subjects with severe renal impairment defined as eGFR <30 mL/min/1.73 m2, the Cmax was essentially unchanged and AUC0-∞ was decreased by less than 10% compared to 8 matched healthy control subjects. Hemodialysis does not result in meaningful removal of tedizolid from systemic circulation, as assessed in subjects with end-stage renal disease (eGFR <15 mL/min/1.73 m2). No dosage adjustment is necessary in patients with renal impairment or patients on hemodialysis.

Geriatric Patients

The pharmacokinetics of tedizolid were evaluated in a Phase 1 study conducted in elderly healthy volunteers (age 65 years and older, with at least 5 subjects at least 75 years old; n=14) compared to younger control subjects (25 to 45 years old; n=14) following administration of a single oral dose of Sivextro 200 mg. There were no clinically meaningful differences in tedizolid Cmax and AUC0-∞ between elderly subjects and younger control subjects. No dosage adjustment of Sivextro is necessary in elderly patients.

Gender

The impact of gender on the pharmacokinetics of Sivextro was evaluated in clinical trials of healthy males and females and in a population pharmacokinetics analysis. The pharmacokinetics of tedizolid were similar in males and females. No dosage adjustment of Sivextro is necessary based on gender.

Drug Interaction Studies

Drug Metabolizing Enzymes

Transformation via Phase 1 hepatic oxidative metabolism is not a significant pathway for elimination of Sivextro.

Neither Sivextro nor tedizolid detectably inhibited or induced the metabolism of selected CYP enzyme substrates, suggesting that drug-drug interactions based on oxidative metabolism are unlikely.

Membrane Transporters

The potential for tedizolid or tedizolid phosphate to inhibit transport of probe substrates of important drug uptake (OAT1, OAT3, OATP1B1, OATP1B3, OCT1, and OCT2) and efflux transporters (P-gp and BCRP) was tested in vitro. No clinically relevant interactions are expected to occur with these transporters except BCRP. Coadministration of multiple oral doses of Sivextro (200 mg once daily) increased the Cmax and AUC of rosuvastatin (10 mg single oral dose), a known BCRP substrate, by approximately 55% and 70%, respectively, in healthy subjects [see Drug Interactions (7)].

Monoamine Oxidase Inhibition

Tedizolid is a reversible inhibitor of monoamine oxidase (MAO) in vitro. The interaction with MAO inhibitors could not be evaluated in Phase 2 and 3 trials, as subjects taking such medications were excluded from the trials.

Adrenergic Agents

Two placebo-controlled crossover studies were conducted to assess the potential of 200 mg oral Sivextro at steady state to enhance pressor responses to pseudoephedrine and tyramine in healthy individuals. No meaningful changes in blood pressure or heart rate were seen with pseudoephedrine. The median tyramine dose required to cause an increase in systolic blood pressure of ≥30 mmHg from pre-dose baseline was 325 mg with Sivextro compared to 425 mg with placebo. Palpitations were reported in 21/29 (72.4%) subjects exposed to Sivextro compared to 13/28 (46.4%) exposed to placebo in the tyramine challenge study.

Serotonergic Agents

Serotonergic effects at doses of tedizolid phosphate up to 30-fold above the human equivalent dose did not differ from vehicle control in a mouse model that predicts serotonergic activity. In Phase 3 trials, subjects taking serotonergic agents including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and serotonin 5-hydroxytryptamine (5-HT1) receptor agonists (triptans), meperidine, or buspirone were excluded.

Microbiology

Tedizolid belongs to the oxazolidinone class of antibacterial drugs.

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).

Aerobic and Facultative Gram-positive Bacteria

The following in vitro data are available, but their clinical significance has not been established. At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to 0.5 mcg/mL for tedizolid. However, the safety and effectiveness of Sivextro in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic and Facultative Anaerobic Gram-positive Bacteria

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.

Diffusion techniques

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.

Quality Control

Standardized susceptibility test procedures require the use of laboratory control microorganisms to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test.1, 2, 3 Standardized tedizolid powder should provide the following range of MIC values noted in Table 6. For the diffusion technique using the 20 mcg tedizolid disk, results within the ranges specified in Table 6 should be observed.