SIVEXTRO (Page 3 of 7)

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.

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