Baxdela (Page 5 of 9)

10 OVERDOSAGE

Treatment of overdose with BAXDELA should consist of observation and general supportive measures. Hemodialysis removed about 19% of delafloxacin and 56% of SBECD (Sulfobutylether β cyclodextrin) after intravenous administration of BAXDELA [see Clinical Pharmacology (12.3)].

11 DESCRIPTION

BAXDELA (delafloxacin) for Injection and BAXDELA (delafloxacin) Tablets contain meglumine salt of delafloxacin, a fluoroquinolone antibacterial. Delafloxacin meglumine is identified chemically as 1-Deoxy-1-(methylamino)-D-glucitol, 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (salt), the chemical structure of which is shown below. The meglumine salt has a molecular weight of 635.97 g/mol, whereas the molecular weight of the delafloxacin free acid is 440.76 g/mol.

Figure 1 Chemical Structure

Chemical Structure
(click image for full-size original)

C18 H12 ClF3 N4 O4 ∙ C7 H17 NO5 M.W. 635.97

BAXDELA is intended for intravenous infusion or oral administration. BAXDELA is supplied as a sterile, lyophilized powder for injection and oral tablets as follows:

BAXDELA for Injection

Each vial of BAXDELA for Injection, 300 mg, is a sterile lyophilized powder that contains 300 mg delafloxacin (equivalent to 433 mg delafloxacin meglumine) and the following inactive ingredients: Edetate disodium (EDTA), (3.4 mg); meglumine (59 mg); sulfobutylether-β-cyclodextrin (2400 mg).

BAXDELA Tablets

Each BAXDELA tablet for oral use contains 450 mg delafloxacin (equivalent to 649 mg delafloxacin meglumine) and the following inactive ingredients: Citric acid anhydrous (5.5 mg); crospovidone (109 mg); magnesium stearate (10 mg); microcrystalline cellulose (417 mg); povidone (34 mg); sodium bicarbonate (140 mg); sodium phosphate monobasic monohydrate (5.5 mg).

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

The antibacterial activity of delafloxacin appears to best correlate with the ratio of area under the concentration-time curve of free delafloxacin to minimal inhibitory concentration (f AUC/MIC) for Gram-positive organisms such as Staphylococcus aureus and Gram-negative organisms such as Escherichia coli based on animal models of infection.

Cardiac Electrophysiology

In a randomized, positive- and placebo-controlled, thorough QT/QTc study, 51 healthy subjects received BAXDELA 300 mg IV, BAXDELA 900 mg IV, oral moxifloxacin 400 mg, or placebo. Neither BAXDELA 300 mg nor BAXDELA 900 mg (three times the intravenous therapeutic dose) had any clinically relevant adverse effect on cardiac repolarization.

Photosensitivity Potential

A study of photosensitizing potential to ultraviolet (UVA and UVB) and visible radiation was conducted in 52 healthy volunteers (originally 13 subjects per treatment group). BAXDELA, at 200 mg/day and 400 mg/day (0.22 and 0.44 times the approved recommended daily oral dosage, respectively) for 7 days, and placebo did not demonstrate clinically significant phototoxic potential at any wavelengths tested (295 nm to 430 nm), including solar simulation. The active comparator (lomefloxacin) demonstrated a moderate degree of phototoxicity at UVA 335 nm and 365 nm and solar simulation wavelengths.

12.3 Pharmacokinetics

The pharmacokinetic parameters of delafloxacin following single- and multiple-dose (every 12 hours) oral (450 mg) and intravenous (300 mg) administration are shown in Table 6. Steady-state was achieved within approximately three days with accumulation of approximately 10% and 36% following IV and oral administration, respectively.

Table 6 Mean (SD) Delafloxacin Pharmacokinetic Parameters Following Single and Multiple Oral and Intravenous Administration
Parameters Tablet Intravenous Injection
Single Dose 450 mg Steady State 450 mg Q12h * Single Dose 300 mg Steady State 300 mg Q12h *
Cmax = maximum concentration; Tmax = time to reach Cmax ; AUC = area under the concentration-time curve; CL = systemic clearance; CL/F = apparent oral clearance; Rac = accumulation ratio
*
Q12h is every 12 hours
Median (range)
AUC is AUCτ (AUC from time 0 to 12 hours) for single dose and multiple-dose administration
§
CL is reported for intravenous injection. CL/F is reported for tablet
Tmax (h) 0.75 (0.5, 4.0) 1.00 (0.50, 6.00) 1.0 (1.0, 1.2) 1.0 (1.0, 1.0)
Cmax (µg/mL) 7.17 (2.01) 7.45 (3.16) 8.94 (2.54) 9.29 (1.83)
AUC (µg∙h/mL) 22.7 (6.21) 30.8 (11.4) 21.8 (4.54) 23.4 (6.90)
CL or CL/F(L/h)§ 20.6 (6.07) 16.8 (6.54) 14.1 (2.81) 13.8 (3.96)
CLr (L/h) 5.89 (1.53) 6.69 (2.19)
Rac 1.36 1.1

Absorption

The absolute bioavailability for BAXDELA 450 mg oral tablet administered as a single dose was 58.8%. The AUC of delafloxacin following administration of a single 450 mg oral (tablet) dose was comparable to that following a single 300 mg intravenous dose. The Cmax of delafloxacin was achieved within about 1 hour after oral administration under fasting condition. Food (kcal: 917, Fat: 58.5%, Protein: 15.4%, Carbohydrate: 26.2%). did not affect the bioavailability of delafloxacin [see Dosage and Administration (2.1)].

Distribution

The steady state volume of distribution of delafloxacin is 30–48 L which approximates total body water. The plasma protein binding of delafloxacin is approximately 84%; delafloxacin primarily binds to albumin. Plasma protein binding of delafloxacin is not significantly affected by renal impairment.

Following IV administration of 7 doses of 300 mg of BAXDELA to 30 healthy volunteers, the mean BAXDELA AUC0-12 (3.6 hr*mcg/mL) in alveolar macrophages was 80% of the free-plasma AUC0-12 , and the mean BAXDELA AUC0-12 (2.8 hr*mcg/mL) in epithelial lining fluid was 70% of the free-plasma AUC0-12.

Elimination

In a mass balance study, the mean half-life for delafloxacin was 3.7 hours (SD 0.7 hour) after a single dose intravenous administration. The mean half-life values for delafloxacin ranged from 4.2 to 8.5 hours following multiple oral administrations. Following administration of a single 300 mg intravenous dose of BAXDELA, the mean clearance (CL) of delafloxacin was 16.3 L/h (SD 3.7 L/h), and the renal clearance (CLr) of delafloxacin accounts for 35-45% of the total clearance.

Metabolism

Glucuronidation of delafloxacin is the primary metabolic pathway with oxidative metabolism representing about 1% of an administered dose. The glucuronidation of delafloxacin is mediated mainly by UGT1A1, UGT1A3, and UGT2B15. Unchanged parent drug is the predominant component in plasma. There are no significant circulating metabolites in humans.

Excretion

After single intravenous dose of 14 C-labeled delafloxacin, 65% of the radioactivity was excreted in urine as unchanged delafloxacin and glucuronide metabolites and 28% was excreted in feces as unchanged delafloxacin. Following a single oral dose of 14 C-labeled delafloxacin, 50% of the radioactivity was excreted in urine as unchanged delafloxacin and glucuronide metabolites and 48% was excreted in feces as unchanged delafloxacin.

Specific Populations

No clinical significance in the pharmacokinetics of delafloxacin was observed based on age, sex, race, weight, body mass index, and disease state (ABSSSI and CABP).

Patients with Hepatic Impairment

No clinically meaningful changes in delafloxacin Cmax and AUC were observed, following administration of a single 300 mg intravenous dose of BAXDELA to patients with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B, and C) compared to matched healthy control subjects.

Patients with Renal Impairment

Following a single intravenous (300 mg) administration of delafloxacin to subjects with mild (eGFR = 51-80 mL/min/1.73 m2), moderate (eGFR = 31–50 mL/min/1.73 m2), severe (eGFR = 15-29 mL/min/1.73 m2) renal impairment, and ESRD on hemodialysis receiving intravenous delafloxacin within 1 hour before and 1 hour after hemodialysis, mean total exposure (AUCt ) of delafloxacin was 1.3, 1.6, 1.8, 2.1, and 2.6-fold higher, respectively than that for matched normal control subjects. The mean dialysate clearance (CLd ) of delafloxacin was 4.21 L/h (SD 1.56 L/h). After about 4 hours of hemodialysis, the mean fraction of administered delafloxacin recovered in the dialysate was about 19% [see Use in Specific Populations (8.7)].

Following a single oral (400 mg) administration of delafloxacin to subjects with mild (eGFR = 51-80 mL/min/1.73 m2), moderate (eGFR = 31-50 mL/min/1.73 m2), or severe (eGFR = 15-29 mL/min/1.73 m2) renal impairment, the mean total exposure (AUCt ) of delafloxacin was about 1.5-fold higher for subjects with moderate and severe renal impairment compared with healthy subjects, whereas total systemic exposures of delafloxacin in subjects with mild renal impairment were comparable with healthy subjects.

In patients with moderate (eGFR = 31–50 mL/min/1.73 m2), or severe (eGFR = 15–29 mL/min/1.73 m2) renal impairment or ESRD on hemodialysis, accumulation of the intravenous vehicle SBECD occurs. The mean systemic exposure (AUC) increased 2-fold, 5-fold, 7.5-fold, and 27-fold for patients with moderate impairment, severe impairment, ESRD on hemodialysis receiving intravenous delafloxacin within 1 hour before, and 1 hour after hemodialysis respectively, compared to the healthy control group. In subjects with ESRD undergoing hemodialysis, SBECD is dialyzed with a clearance of 4.74 L/h. When hemodialysis occurred 1 hour after the BAXDELA infusion in subjects with ESRD, the mean fraction of SBECD recovered in the dialysate was 56.1% over approximately 4 hours.

Geriatric Patients

Following single oral administration of 250 mg delafloxacin (approximately 0.6 times the approved recommended oral dose), the mean delafloxacin Cmax and AUC values in elderly subjects (≥ 65 years) were about 35% higher compared to values obtained in young adults (18 to 40 years). This difference is not considered clinically relevant. A population pharmacokinetic analysis of patients with ABSSSI or CABP indicated that patients over the age of 65 years have slower clearance than younger patients. However, the overall impact on delafloxacin pharmacokinetics is not considered clinically significant and dose adjustment in elderly patients is not warranted.

Male and Female Patients

Following single oral administration of 250 mg delafloxacin (approximately 0.6 times the approved recommended oral dose), the mean delafloxacin Cmax and AUC values in male subjects were comparable to female subjects. Results from a population pharmacokinetic analysis showed that females have a 24% lower AUC than males. This difference is not considered clinically relevant.

Drug Interaction Studies

Drug Metabolizing Enzymes

Delafloxacin at clinically relevant concentrations does not inhibit the cytochrome P450 isoforms CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5 in vitro in human liver microsomes. At a delafloxacin concentration (500 µM) well above clinically relevant exposures, the activity of CYP2E1was increased.

In human hepatocytes, delafloxacin showed no potential for in vitro induction of CYP1A2, 2B6, 2C19, or 2C8 but was a mild inducer of CYP2C9 at a concentration of 100 µM and CYP3A4 at a clinically relevant concentration. Administration of BAXDELA 450 mg every 12 hours for 5 days to healthy male and female subjects (n = 22) prior to and on Day 6 with a single oral 5 mg dose of midazolam (a sensitive CYP3A substrate), did not affect the Cmax and AUC values for midazolam or 1-hydroxy midazolam compared to administration of midazolam alone.

Transporters

Delafloxacin was not an inhibitor of the following hepatic and renal transporters in vitro at clinically relevant concentrations: MDR1, BCRP, OAT1, OAT3, OATP1B1, OATP1B3, BSEP, OCT1 and OCT2. Delafloxacin was not a substrate of OAT1, OAT3, OCT1, OCT2, OATP1B1 or OATP. Delafloxacin was shown to be a substrate of P-gp and BCRP in vitro. The clinical relevance of co-administration of delafloxacin and P-gp and/or BCRP inhibitors is unknown.

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2021. All Rights Reserved.