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FDA News: Issue 28, August 2019

Published on 9/3/2019 6:04:00 AM


FDA Approves XENLETA (Lefamulin) Injection and Tablets for the Treatment of Adults with Community-Acquired Bacterial Pneumonia (CABP)

On August 19, 2019, the US Food and Drug Administration (FDA) approved XENLETA (lefamulin) for the treatment of adults with community-acquired bacterial pneumonia (CABP) caused by the following susceptible microorganisms: Streptococcus pneumoniae, Staphylococcus aureus (methicillin-susceptible isolates), Haemophilus influenzae, Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydophila pneumoniae. To reduce the development of drug-resistant bacteria and maintain the effectiveness of XENLETA and other antibacterial drugs, XENLETA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

The approved recommended dosage of XENLETA is as follows:
  • XENLETA Injection: 150 mg every 12 hours by intravenous infusion over 60 minutes for 5 to 7 days, with the option to switch to XENLETA Tablets 600 mg every 12 hours to complete the treatment course.
  • XENLETA Tablets: 600 mg orally every 12 hours for 5 days.

Administer XENLETA Tablets at least 1 hour before a meal or 2 hours after a meal. XENLETA is contraindicated in patients with known hypersensitivity to lefamulin, pleuromutilin class drugs, or any of the components of XENLETA. Concomitant use of XENLETA Tablets with sensitive CYP3A substrates known to prolong the QT interval is contraindicated.
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Additional information regarding dosage and administration as well as important warnings and precautions about QT prolongation, embryo-fetal toxicity, Clostridium difficile-associated diarrhea, and the risk of the development of drug-resistant bacteria can be found in the full prescribing information linked below.

Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD)
  • MOA: XENLETA is a pleuromutilin antibacterial drug.
  • General PK: Following single-dose intravenous administration, the AUC of lefamulin increased approximately dose-proportionally while the Cmax of lefamulin increased less than dose-proportionally over a dose range of 25 mg (0.17 times the approved dose) to 400 mg (2.67 times the approved dose). Following single-dose oral administration, the AUC of lefamulin increased more than dose proportionally over a dose range of 500 mg (0.8 times the approved dose) to 750 mg (1.25 times the approved dose).
  • Absorption: The mean absolute bioavailability of XENLETA Tablets is approximately 25% and peak lefamulin plasma concentration occurred 0.88 to 2 hours after administration to healthy subjects.
  • Effect of Food: Administration of a single oral dose of 600 mg XENLETA Tablets with a high fat (approximately 50% of total calories from fat), high calorie breakfast (approximately 800-1000 calories) slightly reduced bioavailability. The mean relative reduction to a fasted condition was 22.9% for the Cmax and 18.43% for the AUC0-inf.
  • Distribution: The mean (min to max) steady state volume of distribution of lefamulin is 86.1 L (34.2 to 153 L) in patients with CABP after administration of XENLETA Injection. Mean plasma protein binding of lefamulin ranges from 94.8% at 2.35 mcg/mL to 97.1% at 0.25 mcg/mL in healthy adults.
  • Elimination: The mean (min to max) elimination half-life of lefamulin is approximately 8 hours (3 to 20 h) in patients with CABP. The mean (min to max) total body clearance of lefamulin is 11.9 L/h (2.94 to 30.0 L/h) in patients with CABP after XENLETA Injection administration.
  • Metabolism: Lefamulin is primarily metabolized by CYP3A4.
  • Excretion: In healthy adult subjects, the mean % of total radioactivity excreted in feces was 77.3% (4.2% to 9.1% unchanged) and 88.5% (7.8% to 24.8% unchanged), and in urine was 15.5% (9.6% to 14.1% unchanged) and 5.3% (unchanged not determined) following 150 mg IV or 600 mg oral XENLETA, respectively.
  • Antibacterial Activity: The 24 h free-drug AUC to minimal inhibitory concentration (MIC) ratio has been shown to be the best PK-PD index for the antibacterial activity of lefamulin in animal infection models of Streptococcus pneumoniae and Staphylococcus aureus pneumonia.
  • Cardiac Electrophysiology: The mean change from baseline QTcF (90% two-sided upper confidence interval) values around Tmax on day 3 or 4 were 13.6 ms (15.5 ms) for the150 mg injection administered twice daily as an infusion and 9.3 ms (10.9 ms) for the 600 mg tablet administered twice daily. A concentration dependent QTc prolongation effect of XENLETA was observed in adult patients with CABP.
Drug Interactions
  • Strong and Moderate CYP3A Inducers or P-gp Inducers: Avoid concomitant use of XENLETA Injection and XENLETA Tablets with strong and moderate CYP3A4 inducers or P-gp inducers unless the benefit outweighs the risks. Concomitant use of XENLETA Injection or XENLETA Tablets with strong CYP3A4 inducers or P-gp inducers decreases lefamulin AUC and Cmax, which may reduce the efficacy of XENLETA.
  • Strong and Moderate CYP3A Inhibitors or P-gp Inhibitors: Avoid concomitant use of XENLETA Tablets with strong CYP3A inhibitors or P-gp inhibitors. Monitor for adverse effects of XENLETA Tablets when administered concomitantly with moderate CYP3A inhibitors or P-gp inhibitors. Concomitant use of XENLETA Tablets with strong CYP3A inhibitors or P-gp inhibitors increases lefamulin AUC, which may increase the risk of adverse reactions with XENLETA Tablets.
  • CYP3A4 Substrates: Concomitant use with CYP3A substrates known to prolong the QT interval is contraindicated. Concomitant use of sensitive CYP3A substrates with XENLETA Tablets requires close monitoring for adverse effects of these drugs. Concomitant use of XENLETA Tablets with sensitive CYP3A4 substrates increases the AUC and Cmax of CYP3A4 substrates, which may increase the risk of toxicities associated with cardiac conduction. Concomitant use of XENLETA Injection with CYP3A4 substrates does not affect the exposure of CYP3A4 substrates.
  • Drugs that Prolong QT: Avoid concomitant use of XENLETA Injection and XENLETA Tablets with other drugs that effect cardiac conduction (for example, Class IA and III antiarrhythmics, antipsychotics, erythromycin, moxifloxacin, tricyclic antidepressants). XENLETA has the potential to prolong the QT interval of the electrocardiogram (ECG) in some patients. The PD interaction potential to prolong the QT interval between XENLETA and other drugs that effect cardiac conduction is unknown.
Use in Specific Populations
No clinically significant differences in the pharmacokinetics of XENLETA were observed based on age, sex, race, weight, or renal impairment including patients receiving hemodialysis.

Hepatic Impairment
Monitor patients with hepatic impairment for adverse reactions associated with XENLETA Injection and Tablets throughout the treatment period.
  • XENLETA Injection: Reduce the dosage of XENLETA Injection to 150 mg infused intravenously over 60 minutes every 24 hours for patients with severe hepatic impairment (Child-Pugh Class C). No dosage adjustment of XENLETA Injection is needed for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Following administration of XENLETA Injection, the half-life of lefamulin is prolonged in subjects with severe hepatic impairment compared to that in subjects with normal hepatic function (17.5 h versus 11.5 h). Protein binding of lefamulin is reduced in subjects with hepatic impairment. Therefore, unbound (biologically active) lefamulin concentrations increased with the degree of hepatic impairment.
  • XENLETA Tablets: XENLETA Tablets have not been studied in and are not recommended for patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment. No dosage adjustment of XENLETA Tablets is needed for patients with mild hepatic impairment (Child-Pugh Class A).
Lactation
A lactating woman should pump and discard human milk for the duration of treatment with XENLETA and for 2 days after the final dose because of the potential for serious adverse reactions, including QT prolongation.

Efficacy and Safety
Efficacy of XENLETA was demonstrated in two multicenter, multinational, double-blind, double-dummy, non-inferiority trials. In both trials, efficacy was determined by Early Clinical Response (ECR) at 72 to 120 hours after the first dose in the Intent-to-treat (ITT) Analysis Set, which comprised all randomized patients. Patients entered the trials with at least three of four symptoms consistent with CABP (cough, sputum production, chest pain, and/or dyspnea). Response was defined as survival with improvement of at least two symptoms, no worsening of any symptom, and no receipt of non-study antibacterial treatment for CABP. Additional information regarding efficacy trials can be found in the full prescribing information linked below.

The most common adverse reactions (incidence ≥ 2%) are as follows:
  • XENLETA Injection: Administration site reactions, hepatic enzyme elevation, nausea, hypokalemia, insomnia, headache.
  • XENLETA Tablets: Diarrhea, nausea, vomiting, hepatic enzyme elevation.

Full prescribing information is available at https://go.usa.gov/xVgjR.

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. 

A non-comprehensive list of examples of clinical substrates, inhibitors and inducers for metabolic and transporter system related interactions may be found at https://go.usa.gov/xXY9C.

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/report.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

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