Xenleta (lefamulin)

What is Xenleta, and how does it work?

Xenleta is a semi-synthetic antibacterial agent for oral and intravenous administration. Xenleta is indicated 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.

What are the side effects of Xenleta?

The following clinically significant adverse reactions are described elsewhere in the labeling:

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

  • Xenleta was evaluated in two clinical trials in CABP patients (Trial 1 and Trial 2).
  • Across the two trials, a total of 641 patients were treated with
    Xenleta.
  • Trial 1 (intravenous [IV] to oral dosing switch trial) enrolled 551 adult patients, 276 randomized to
    Xenleta (273 received at least one dose of Xenleta) and 275 randomized to moxifloxacin (273 received at least one dose of moxifloxacin).
  • Trial 2 (oral dosing only trial) enrolled 738 adult patients, 370 randomized to
    Xenleta (368 received at least one dose of Xenleta) and 368 randomized to moxifloxacin (all 368 received at least one dose of moxifloxacin).
  • Trial 1 enrolled patients with Pneumonia Outcomes Research Team (PORT) Risk Class III-V. The mean duration of intravenous treatment was 6 days; the mean total duration of treatment was 7 days.
  • Trial 2 enrolled patients with PORT Risk Class II-IV. The mean duration of treatment was 5 days for
    Xenleta and 7 days for moxifloxacin.
  • In Trial 1 and Trial 2 (pooled), the median age of patients treated with
    Xenleta was 61 (range 19-97) years; 42% of patients were 65 years or older and 18% were 75 years or older.
  • Patients were predominantly male (58%) and white (79%) and had a median body mass index (BMI) of 26.0 (range 13.0-56.8) kg/m2.
  • Approximately 52% of Xenleta-treated patients had creatinine clearance (CrCl) <90 mL/min.
Serious Adverse Reactions And Adverse Reactions Leading To Discontinuation
  • In Trial 1 and Trial 2 (pooled), serious adverse reactions occurred in 36/641 (5.6%) patients treated with
    Xenleta and 31/641 (4.8%) patients treated with moxifloxacin.
  • Treatment was discontinued due to an adverse reaction in 21/641 (3.3%) patients treated with
    Xenleta and 21/641 (3.3%) patients treated with moxifloxacin.
  • Death within 28 days occurred in 8/641 (1.2%) patients treated with
    Xenleta and 7/641 (1.1%) patients treated with moxifloxacin.
Most Common Adverse Reactions

Table 2 and Table 3 include adverse reactions occurring in ≥2% of patients receiving
Xenleta in Trials 1 and 2.

Table 2: Adverse Reactions Occurring in ≥2% of Patients Receiving
Xenleta in Trial 1

Adverse Reaction
Trial 1
IV ± Oral Dosing

Xenleta
N=273
Moxifloxacin
N=273

Administration site reactions*
7%
3%

Hepatic enzyme elevation**
3%
3%

Nausea
3%
2%

Hypokalemia
3%
2%

Insomnia
3%
2%

Headache
2%
2%

*Administration site reactions include infusion site pain, infusion site phlebitis, and injection site reaction.
**Hepatic enzyme elevation includes alanine aminotransferase increased, aspartate aminotransferase increased, and liver function test increased.

Table 3: Adverse Reactions Occurring in ≥2% of Patients Receiving
Xenleta in Trial 2

Adverse Reaction
Trial 2 Oral Dosing

Xenleta
N=368
Moxifloxacin
N=368

Diarrhea
12%
1%

Nausea
5%
2%

Vomiting
3%
1%

Hepatic enzyme elevation**
2%
2%

**Hepatic enzyme elevation includes alanine aminotransferase increased, aspartate aminotransferase increased, and liver function test increased.

Selected Adverse Reactions Occurring In Less Than 2% Of Patients Receiving
Xenleta In Trials 1 And 2

What is the dosage for Xenleta?

Recommended Dosage

For treatment of adults with CABP, the recommended dosage of Xenleta is
described in Table 1 below. For patients with severe hepatic impairment, dosage
adjustment is required.

Table 1: Dosage of Xenleta in Adult CABP Patients

Dosage
Treatment Duration

150 mg every 12 hours by intravenous infusion over 60 minutes*
5 to 7 days

600 mg orally every 12 hours
5 days

*With the option to switch to Xenleta Tablets 600 mg every 12 hours to complete the treatment course.

Dosage Adjustment For Patients With 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.
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).

Important Administration Instructions

Xenleta Injection
  • Administer Xenleta Injection by intravenous infusion over 60 minutes.
    Must dilute in a 250 mL solution of 10 mM citrate buffered 0.9% sodium
    chloride for injection supplied with Xenleta Injection before use.
Xenleta Tablets
  • Take Xenleta Tablets at least 1 hour before a meal or 2 hours after a
    meal. Swallow Xenleta Tablets whole with water (6 to 8 ounces).
  • Do not crush or divide Xenleta Tablets.
Missed Dose
  • If a dose is missed, the patient should take the dose as soon as possible and anytime up to 8 hours prior to the next scheduled dose. If less than 8 hours remain before the next scheduled dose, do not take the missed dose, and resume dosing at the next scheduled dose.





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What drugs interact with Xenleta?

Effect Of Other Drugs On Xenleta

Strong And Moderate CYP3A Inducers Or P-Gp Inducers
  • Concomitant use of oral or intravenous Xenleta with strong CYP3A4
    inducers or P-gp inducers decreases lefamulin AUC and Cmax,which may reduce the efficacy of
    Xenleta.
  • 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.
Strong And 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.
  • 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.

Effect Of Xenleta On Other Drugs

CYP3A4 Substrates
  • 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 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 (for example, alprazolam, diltiazem, verapamil, simvastatin, vardenafil).
  • Concomitant use of Xenleta Injection with CYP3A4 substrates does not affect the exposure of CYP3A4 substrates.

Drugs That Prolong QT

The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between
Xenleta and other drugs that effect cardiac conduction is unknown. Therefore, avoid concomitant use of
Xenleta Injection and Xenleta Tablets with such drugs (for example, Class IA and III antiarrhythmics, antipsychotics, erythromycin, moxifloxacin, tricyclic antidepressants).

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Is Xenleta safe to use while pregnant or breastfeeding?

  • Based on findings from animal studies, lefamulin may cause fetal harm when administered to pregnant women.
  • There are no available data on the use of Xenleta in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.
  • There are no data on the presence of Xenleta in human milk, its effects on the breastfed infant, or its effects on milk production. Animal studies indicate that lefamulin was concentrated in the milk of lactating rats.
  • When a drug is present in animal milk, it is likely that the drug will be present in human milk.
  • Because of the potential for serious adverse reactions, including QT prolongation, a woman should pump and discard human milk for the duration of treatment with
    Xenleta and for 2 days after the final dose.

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