| FDA Approves BAXDELA (Delafloxacin) in Adults for the Treatment of Acute Bacterial Skin and Skin Structure Infections Caused by Designated Susceptible Bacteria |
On June 19, 2017, the U.S. Food and Drug Administration (FDA) approved BAXDELA (delafloxacin) in adults for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible gram-positive and gram-negative organisms listed in the approved product labeling linked below. To reduce the development of drug-resistant bacteria and maintain the effectiveness of BAXDELA and other antibacterial drugs, BAXDELA should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria.
The approved recommended dosage regimens of BAXDELA are:
- 300 mg of BAXDELA for Injection every 12 hours over 60 minutes by intravenous infusion for 5 to 14 days or,
- 300 mg of BAXDELA for Injection every 12 hours over 60 minutes by intravenous infusion, then switch to a 450 mg BAXDELA tablet orally every 12 hours at the discretion of the physician for a total duration of 5 to 14 days or,
- 450 mg BAXDELA tablet orally every 12 hours for a total duration of 5 to 14 days.
Reduce the dose in patients with severe renal impairment (eGFR 15-29 mL/min/1.73 m2) receiving intravenous BAXDELA and closely monitor serum creatinine levels and eGFR. If serum creatinine level increases occur, consider switching to oral BAXDELA. Discontinue BAXDELA if eGFR decreases to < 15 mL/min/1.73 m2.
BAXDELA carries a boxed warning about serious adverse reactions including tendinitis, tendon rupture, peripheral neuropathy, central nervous system effects, and exacerbation of muscle weakness in patients with myasthenia gravis. Discontinue BAXDELA immediately and avoid the use of fluoroquinolones, including BAXDELA, in patients who experience any of these serious adverse reactions. Avoid BAXDELA in patients with known history of myasthenia gravis.
Mechanism of Action (MOA), General Pharmacokinetics (PK), and Pharmacodynamics (PD)
- MOA: BAXDELA is a fluoroquinolone antibacterial drug. The antibacterial activity of delafloxacin is due to the inhibition of bacterial topoisomerase IV and DNA gyrase (topoisomerase II) enzymes required for bacterial DNA replication, transcription, repair, and recombination. BAXDELA exhibits a concentration-dependent bactericidal activity against gram-positive and gram-negative bacteria in vitro.
- Accumulation: Steady-state was achieved within approximately 3 days with accumulation of approximately 10% and 36% following intravenous and oral administration, respectively.
- Absorption: The absolute bioavailability for single dose BAXDELA 450 mg oral tablet 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 single or multiple oral and intravenous administrations.
- Plasma Protein Binding: The plasma protein binding of delafloxacin was approximately 84%, primarily to albumin, and not significantly affected by renal impairment.
- Half-Life: 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.
- Elimination: 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: Mediated mainly by UGT1A1, UGT1A3, and UGT2B15, glucuronidation of delafloxacin is the primary metabolic pathway with oxidative metabolism representing about 1% of an administered dose. There are no significant circulating metabolites in humans.
- Excretion: After single intravenous dose of radiolabeled delafloxacin, 65% of 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 radiolabeled delafloxacin, 50% of radioactivity was excreted in urine as unchanged delafloxacin and glucuronide metabolites and 48% was excreted in feces as unchanged delafloxacin.
Drug Interactions
Fluoroquinolones form chelates with alkaline earth and transition metal cations. Oral administration of BAXDELA with antacids containing aluminum or magnesium, with sucralfate, with metal cations such as iron, or with multivitamins containing iron or zinc, or with formulations containing divalent and trivalent cations such as didanosine buffered tablets for oral suspension or the pediatric powder for oral solution, may substantially interfere with the absorption of BAXDELA, resulting in systemic concentrations considerably lower than desired. Take oral BAXDELA at least 2 hours before or 6 hours after these chelation agents (e.g., antacids, sucralfate, metal cations, multivitamins).
Fluoroquinolones form chelates with alkaline earth and transition metal cations. Oral administration of BAXDELA with antacids containing aluminum or magnesium, with sucralfate, with metal cations such as iron, or with multivitamins containing iron or zinc, or with formulations containing divalent and trivalent cations such as didanosine buffered tablets for oral suspension or the pediatric powder for oral solution, may substantially interfere with the absorption of BAXDELA, resulting in systemic concentrations considerably lower than desired. Take oral BAXDELA at least 2 hours before or 6 hours after these chelation agents (e.g., antacids, sucralfate, metal cations, multivitamins).
Do not co-administer BAXDELA with any solution containing multivalent cations (e.g., calcium or magnesium) through the same intravenous line.
Use in Specific Populations
Age, sex, race, weight, body mass index, disease state (ABSSSI), and hepatic impairment did not significantly impact pharmacokinetics of delafloxacin.
Age, sex, race, weight, body mass index, disease state (ABSSSI), and hepatic impairment did not significantly impact pharmacokinetics of delafloxacin.
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 end stage renal disease (ESRD; eGFR < 15 mL/min/1.73 m2) on hemodialysis within 1 hour before and 1 hour after hemodialysis, delafloxacin mean total exposure (AUCt) was 1.3, 1.6, 1.8, 2.1, and 2.6-fold higher, respectively than that for matched normal control subjects. In subjects with severe renal impairment or ESRD, accumulation of the intravenous vehicle, sulfobutylether-β-cyclodextrin (SBECD), occurred. Following a single oral (400 mg) dose, delafloxacin AUCt was comparable between subjects with mild renal impairment and healthy subjects, and about 1.5-fold higher for subjects with moderate and severe renal impairment compared with healthy subjects.
- No BAXDELA dosage adjustment is necessary in patients with mild to moderate renal impairment (eGFR 30-89 mL/min/1.73 m2) in patients receiving intravenous or oral administration.
- The dose of intravenous BAXDELA in patients with severe renal impairment (eGFR 15-29 mL/min/1.73 m2) should be decreased to 200 mg by intravenous infusion every 12 hours, and serum creatinine levels and eGFR should be closely monitored. If serum creatinine level increases, consider switching to oral BAXDELA. If eGFR decreases to < 15 mL/min/1.73 m2, BAXDELA should be discontinued.
- The dose of oral BAXDELA in patients with severe renal impairment is 450 mg orally every 12 hours.
- Neither intravenous nor oral BAXDELA is recommended in patients with ESRD including hemodialysis.
Efficacy and Safety
A total of 1510 adults with ABSSSI were randomized in 2 multicenter, multinational, double-blind, double-dummy, non-inferiority trials. Trial 1 compared the approved recommended intravenous dosage of BAXDELA to a comparator. In Trial 2, patients received 6 doses of the approved recommended intravenous dosage then made a mandatory switch to the recommended oral BAXDELA dosage. In both studies, the comparator was the intravenous combination of vancomycin 15 mg/kg actual body weight and aztreonam. Aztreonam therapy was discontinued if no gram-negative pathogens were identified in the baseline cultures. In both Trials 1 and 2, the objective clinical response at 48 to 72 hours post initiation of treatment was defined as ≥ 20% decrease in lesion size as determined by digital planimetry of the leading edge of erythema. The percentage of responders in Trial 1 was 78.2% in the treatment arm compared to 80.9% in the comparator arm with a treatment difference of -2.6% (2-sided 95% CI: -8.8, 3.6). The percentage of responders in Trial 2 was 83.7% in the treatment arm compared to 80.6% in the comparator arm with a treatment difference of 3.1% (2-sided 95% CI: -2.0, 8.3).
A total of 1510 adults with ABSSSI were randomized in 2 multicenter, multinational, double-blind, double-dummy, non-inferiority trials. Trial 1 compared the approved recommended intravenous dosage of BAXDELA to a comparator. In Trial 2, patients received 6 doses of the approved recommended intravenous dosage then made a mandatory switch to the recommended oral BAXDELA dosage. In both studies, the comparator was the intravenous combination of vancomycin 15 mg/kg actual body weight and aztreonam. Aztreonam therapy was discontinued if no gram-negative pathogens were identified in the baseline cultures. In both Trials 1 and 2, the objective clinical response at 48 to 72 hours post initiation of treatment was defined as ≥ 20% decrease in lesion size as determined by digital planimetry of the leading edge of erythema. The percentage of responders in Trial 1 was 78.2% in the treatment arm compared to 80.9% in the comparator arm with a treatment difference of -2.6% (2-sided 95% CI: -8.8, 3.6). The percentage of responders in Trial 2 was 83.7% in the treatment arm compared to 80.6% in the comparator arm with a treatment difference of 3.1% (2-sided 95% CI: -2.0, 8.3).
Most common adverse reactions (≥ 2%) are diarrhea, nausea, headache, transaminase elevations, and vomiting.
Full prescribing information is available at https://go.usa.gov/xN6bQ.
Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/
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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.
FDA/Center for Drug Evaluation and Research (CDER)
Office of Translational Sciences
Office of Clinical Pharmacology
Email: ocp@fda.hhs.gov
Office of Translational Sciences
Office of Clinical Pharmacology
Email: ocp@fda.hhs.gov
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