SIVEXTRO: Package Insert and Label Information (Page 2 of 4)

7 DRUG INTERACTIONS

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. [See Clinical Pharmacology (12.3).]

8 USE IN SPECIFIC POPULATIONS

8.1 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 [GD] 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).

8.2 Lactation

Risk Summary

There is no information on the presence of tedizolid in human milk. Tedizolid is present in rat milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. There are no data on the effects of SIVEXTRO on the breastfed child or on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SIVEXTRO and any potential adverse effects on the breastfed child from SIVEXTRO or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness of SIVEXTRO for the treatment of ABSSSI have been established in pediatric patients aged 12 years and older. 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 aged 12 years and older [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)].

Safety and effectiveness of SIVEXTRO in pediatric patients below the age of 12 years 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.

10 OVERDOSAGE

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.

11 DESCRIPTION

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 C17 H16 FN6 O6 P and its molecular weight is 450.32. Its structural formula is:

Chemical Structure
(click image for full-size original)

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

SIVEXTRO for injection is a sterile, white to off-white sterile lyophilized powder supplied in a clear glass single-dose vial. Each vial contains 200 mg of tedizolid phosphate and the inactive ingredient, mannitol (105 mg). Sodium hydroxide and hydrochloric acid are used as needed for pH adjustment. When reconstituted as directed with 4 mL of Sterile Water for Injection, each mL contains 50 mg of tedizolid phosphate. The pH of the reconstituted solution is 7.4 to 8.1.

12 CLINICAL PHARMACOLOGY

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.

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

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 5.

Table 5: Mean (Standard Deviation) Tedizolid Pharmacokinetic Parameters Following Single and Multiple Oral and Intravenous Administration of 200 mg Once-Daily Tedizolid Phosphate
Pharmacokinetic Parameters of Tedizolid * Oral Intravenous
Single Dose Steady State Single Dose Steady State
*
Cmax , maximum concentration; Tmax , time to reach Cmax ; AUC, area under the concentration-time curve; CL, systemic clearance; CL/F, apparent oral clearance
Median (range)
AUC is AUC0- (AUC from time 0 to infinity) for single-dose administration and AUC0-24 (AUC from time 0 to 24 hours) for multiple-dose administration
Cmax (mcg/mL) 2.0 (0.7) 2.2 (0.6) 2.3 (0.6) 3.0 (0.7)
Tmax (hr) 2.5 (1.0 — 8.0) 3.5 (1.0 — 6.0) 1.1 (0.9 — 1.5) 1.2 (0.9 — 1.5)
AUC (mcg hr/mL) 23.8 (6.8) 25.6 (8.5) 26.6 (5.2) 29.2 (6.2)
CL or CL/F (L/hr) 7.5 (2.3) 6.9 (1.7) 6.4 (1.2) 5.9 (1.4)

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.

Elimination

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 14 C-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.

Patients with 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 adult 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.

Patients with Renal Impairment

Following administration of a single 200 mg intravenous dose of SIVEXTRO to 8 adult 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 adult 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.

Male and Female Patients

The impact of gender on the pharmacokinetics of SIVEXTRO was evaluated in clinical trials of adult 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.

Pediatric Patients

Compared to adult patients, tedizolid exposures are higher in pediatric patients 12 to <18 years of age following multiple dose administration of IV or oral SIVEXTRO (geometric mean Cmax 3.13 vs. 2.00 mcg/mL, AUC24h 28.6 vs. 21.0 mcg*h/mL); however, this increase in exposure is not considered clinically significant.

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 adult 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 adults. 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%) adult 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.

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