Xenleta (lefamulin acetate 600 mg) Dailymed

6 Adverse Reactions

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

• QT Prolongation [see Warnings and Precautions (5.1)].
• Clostridioides difficile-associated Diarrhea [see Warnings and Precautions (5.3)].

Most common adverse reactions (incidence ≥2%) are:

• XENLETA Injection: administration site reactions, hepatic enzyme elevation, nausea, hypokalemia, insomnia, headache. (6.1)
• XENLETA Tablets: diarrhea, nausea, vomiting, hepatic enzyme elevation. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Nabriva Therapeutics US, Inc. at 1-855-5NABRIVA or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 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

*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.
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%

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

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

Selected Adverse Reactions Occurring in Less Than 2% of Patients Receiving XENLETA in Trials 1 and 2

Blood and Lymphatic System Disorders: anemia, thrombocytopenia

Cardiac Disorders: atrial fibrillation, palpitations

Gastrointestinal Disorders: abdominal pain, constipation, dyspepsia, epigastric discomfort, erosive gastritis

Infections and Infestations: Clostridioides difficile colitis, oropharyngeal candidiasis, vulvovaginal candidiasis

Investigations: alkaline phosphatase increased, creatine phosphokinase increased, electrocardiogram QT prolonged, gamma-glutamyl transferase increased

Nervous System Disorders: somnolence

Psychiatric Disorders: anxiety

Renal and Urinary Disorders: urinary retention

XENLETA Injection
Strong or moderate CYP3A inducers or P-gp inducers	Avoid XENLETA unless the benefit outweighs the risk. Monitor for reduced efficacy. (7.1)
XENLETA Tablets
Strong or moderate CYP3A inducers or P-gp inducers	Avoid XENLETA unless the benefit outweighs the risk. Monitor for reduced efficacy. (7.1)
Strong CYP3A inhibitors or P-gp inhibitors	Avoid XENLETA. (7.1)
Moderate CYP3A inhibitors or P-gp inhibitors	Monitor for adverse reactions. (7.1)
CYP3A substrates that prolong the QT interval	Concomitant use is contraindicated. (4.2, 7.2)
Midazolam and other sensitive CYP3A substrates	Monitor for adverse reactions. (7.2)

7.1 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 C_max [see Clinical Pharmacology ( 12.3 )] ,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 [see Clinical Pharmacology ( 12.3 )] , 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.

7.2 Effect of XENLETA on Other Drugs

CYP3A4 Substrates

Concomitant use of XENLETA Tablets with sensitive CYP3A4 substrates increases the AUC and C_max of CYP3A4 substrates [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of toxicities associated with cardiac conduction. Concomitant use with CYP3A substrates known to prolong the QT interval is contraindicated [see Contraindications (4.2)]. 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.

7.3 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).

8 Use In Specific Populations

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. (8.2)

8.1 Pregnancy

Risk Summary

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.

Animal studies indicate that intravenous administration of lefamulin during organogenesis resulted in an increased incidence of prenatal mortality at mean maternal exposures 0.9 times the mean exposure in clinical patients (based on AUC_0-24h), decreased fetal body weights, apparent delay in sexual maturation that suggest treatment-related developmental delay, and malformations in rats at maternal exposures greater than 0.4 times the mean exposure in CABP patients for which the litter incidence was nonexistent in concurrent controls and rare (0 to approximately 0.3%) in historical controls. Decreased ossification was seen in fetuses at all doses in a dose-related manner, suggestive of developmental delay (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 to 4% and 15 to 20%, respectively.

There is a pregnancy pharmacovigilance program for XENLETA. If XENLETA is inadvertently administered during pregnancy or if a patient becomes pregnant while receiving XENLETA, healthcare providers should report XENLETA exposure by calling 1-855-5NABRIVA to enroll.
Data

Animal Data

In a prenatal and postnatal development study in rats treated from the beginning of organogenesis through lactation (Gestation Day [GD] 6 through lactation day 21), the percent of live births was reduced (87.4% compared with the concurrent control of 98.7%) in the high dose group of 100 mg/kg/day (0.9 times the mean exposure in CABP patients treated IV). Equivocal findings in that study were indicative of early post-natal mortality and apparent developmental delay that may be related to pre-natal effects.

In the rat embryo-fetal development study of IV lefamulin during organogenesis (GD 6-17), findings included late resorptions in the high-dose group and malformations (cleft palate/jaw/vertebral malformations at the mid and high doses and enlarged ventricular heart chamber with a thin ventricular wall at the high dose) for which the litter incidence was nonexistent in concurrent controls and rare in historical controls (0 to approximately 0.3%). Decreased or no ossification in a number of skeletal elements in all treated groups may indicate treatment-related developmental delay at all doses. The mean exposure at the lowest dose was approximately 0.4 times the mean exposure in CABP patients treated IV. The main human metabolite, 2R-hydroxy lefamulin, was evaluated in an embryo-fetal development study in rats after IV administration and was also associated with the same cardiac malformation seen in the above study, enlarged ventricular heart chamber with or without a thin ventricular wall (which could be associated with undetected valve or great vessel anomalies).

In the rabbit embryo-fetal development study of IV lefamulin during organogenesis (GD 6-18), low numbers of live fetuses in utero in treated groups limited evaluation of the study. Additional findings at the high dose included decreased fetal weight and decreased or no ossification of skeletal elements, which may be indicative of developmental delay. A NOAEL was not determined. The lowest dose (not fully evaluated due to fetal mortality) would correspond to a mean exposure approximately 0.1 times the mean exposure in CABP patients.

Results of animal studies indicate that lefamulin crosses the placenta and is found in fetal tissues. Following a single intravenous administration of 30 mg/kg radio-labelled lefamulin to pregnant female rats on Day 17 of gestation, radioactivity was visible in fetal tissue, with greatest concentrations measured in the placenta and fetal liver (34.3 and 8.26 mcg equivalents/g, respectively) compared to 96.6 mcg equivalents/g in the maternal liver. Radioactivity in fetal tissues generally declined rapidly, and radioactivity associated with the fetus itself was below the limit of quantification by 12 hours post-dose. Radioactivity in the placenta declined rapidly and was below the limit of quantification by 24 hours after dosing. Concentrations of radioactivity in the amniotic sac remained measurable at the final sampling time (72 hours), peaking at 6 hours post-dose. The amniotic fluid did not contain radioactivity at any time after dose administration.

8.2 Lactation

Risk Summary

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 (see Data ). 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.
Data

Administration of a single intravenous dose of 30 mg/kg radio-labelled lefamulin to lactating rats resulted in maximal mean concentrations of radioactivity in plasma and milk at 0.25-hour post-dose (3.29 and 10.7 mcg equivalents/g, respectively) that were markedly reduced at 24 hours post-dose (0.00663 and 0.0700 mcg equivalents/g, respectively). Milk/plasma ratios increased from 3.27 at 0.25-hour post-dose to 8.33 at 6 hours post-dose. These data indicate that pups would be exposed to lefamulin and its metabolites in maternal milk.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Verify pregnancy status in females of reproductive potential.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with XENLETA and for 2 days after the final dose. XENLETA may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

8.4 Pediatric Use

The safety and effectiveness of XENLETA in patients less than 18 years of age has not yet been established.

8.5 Geriatric Use

Of the 646 patients randomized to XENLETA in Trials 1 and 2, 268 (41.5%) were ≥65 years of age. Early clinical response (ECR) rates in the subgroup of patients ≥65 were similar to ECR rates in subjects <65 years of age and comparable across treatment groups (XENLETA versus moxifloxacin).

The adverse reaction profiles in patients ≥65 years and in patients <65 years of age were similar. The percentage of patients in the XENLETA group who had at least one adverse reaction was 30% in patients ≥65 years and 38% in patients <65 years.

8.6 Hepatic Impairment

XENLETA Injection

Dosage of XENLETA Injection should be reduced by extending the dosing interval 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 patients with hepatic impairment. It is not recommended to use XENLETA Tablets for patients with moderate or severe hepatic impairment [see Dosage and Administration (2.2) and Clinical Pharmacology ( 12.3 )].

8.7 Renal Impairment

No dosage adjustment of XENLETA is warranted in patients with renal impairment, including those on hemodialysis.

10 Overdosage

Treatment of overdose with XENLETA should consist of observation and general support measures. Lefamulin and its primary metabolite are not dialyzable.

11 Description

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

XENLETA, a pleuromutilin derivative, is available as 14-O-{[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin in the form of an acetic acid salt (acetate). It is a chemical substance with a molecular weight of 567.79 grams per mole. Its empirical formula is C₃₀H₄₉NO₇S and its chemical structure is:



XENLETA Tablets for oral administration are available as blue, oval, film-coated tablets containing 671 mg lefamulin acetate equivalent to 600 mg lefamulin. The inactive ingredients are colloidal silicon dioxide, croscarmellose sodium, FD&C Blue No 2 aluminum lake, ferrosoferric oxide, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol (partially hydrolyzed), povidone K30, shellac glaze, talc, and titanium dioxide.

XENLETA Injection supplied as a sterile injection for intravenous use is available as a clear colorless solution in a glass vial containing 168 mg of lefamulin acetate equivalent to 150 mg of lefamulin in 15 mL of 0.9% sodium chloride. This is equivalent to 10 mg/mL lefamulin. The inactive ingredients are sodium chloride and water for injection.

XENLETA Injection must be diluted with the diluent supplied with XENLETA Injection, before administration by intravenous infusion. Each supplied diluent infusion bag contains 250 mL of 10 mM citrate buffered (pH 5) 0.9% sodium chloride. The diluent is a clear, colorless solution. The inactive ingredients are citric acid anhydrous, sodium chloride, trisodium citrate dihydrate, and water for injection. Each 100 mL contains: sodium chloride 900 mg, trisodium citrate dihydrate 200 mg, and citric acid anhydrous 61.5 mg in water for injection. Electrolytes per 1000 mL: sodium 174 mEq; chloride 154 mEq. The osmolality is 280-340 mOsm/kg and the pH is 4.5-5.5.

12 Clinical Pharmacology

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

The 24 h free-drug AUC to minimal inhibitory concentration (MIC) ratio has been shown to be the best Pharmacokinetic-Pharmacodynamic (PK-PD) index for the antibacterial activity of lefamulin in animal infection models of Streptococcus pneumoniae and Staphylococcus aureus pneumonia.

Cardiac Electrophysiology

The QTcF interval prolongation risk of XENLETA was evaluated using 2 randomized, double-blind, double-dummy, active controlled (moxifloxacin 400 mg once daily), parallel group, trials (Trials 1 and 2) in adult patients with CABP. A concentration dependent QTc prolongation effect of XENLETA was observed. The mean change from baseline QTcF (90% two-sided upper confidence interval) values around T_max on day 3 or 4 were 13.6 ms (15.5 ms) for 150 mg injection administered twice daily as infusion and 9.3 ms (10.9 ms) for 600 mg tablet administered twice daily. The mean change from baseline QTcF (90% two-sided upper confidence interval) values around T_max for the moxifloxacin randomized comparison arm on day 3 or 4 were 16.4 ms (18.3 ms) for 400 mg injection administered once daily as infusion and 11.6 ms (13.2 ms) for 400 mg tablet administered once daily.

12.3 Pharmacokinetics

Following single-dose intravenous administration, the AUC of lefamulin increased approximately dose-proportionally while the C_max 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).

Pharmacokinetic (PK) parameters of lefamulin following administration of XENLETA Injection or Tablets to patients with CABP are uled in Table 4.

The mean lefamulin AUC_0-24h and C_max in patients with CABP were 73% and 30% higher, respectively, compared with healthy subjects.

Table 4: Pharmacokinetic (PK) Parameters of Lefamulin Following Single or Multiple Dose (Every 12 Hours) XENLETA Administered as 150 mg (Infused Over 60 Minutes) Intravenously (IV) or 600 mg Orally in Patients with CABP ^a

a Based on population PK modeling (Trial 1 for IV administration and Trial 2 for oral administration) b Cmax=maximum plasma concentration; Cmin=trough plasma concentration; AUC0–24h=area under the plasma concentration-time curve from time zero to 24 hours c Dose administered under fasting conditions (1 hour before or 2 hours after a meal)
PK Parameters b	Administration Route	Arithmetic Mean (% CV)
		Day 1	Steady State
Cmax (mcg/mL)	IV	3.50 (11.7)	3.60 (14.6)
	Oral c	2.24 (36.4)	2.24 (37.1)
Cmin (mcg/mL)	IV	0.398 (68.1)	0.573 (89.4)
	Oral c	0.593 (67.3)	0.765 (75.7)
AUC0-24h (mcg·h/mL)	IV	27.0 (31.8)	28.6 (46.9)
	Oral c	30.7 (45.0)	32.7 (49.2)

Absorption

The mean oral 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

The concomitant 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 for oral XENLETA (fasted vs. fed) was on average 22.9% [90% CI: 12.2; 32.3] for the C_max and 18.43% [90% CI: 11.7; 24.7] for the AUC_0-inf.

Distribution

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.

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.

Following a single IV administration of lefamulin 150 mg to healthy subjects, the highest lefamulin epithelial lining fluid (ELF) concentrations were observed at the end of infusion. The mean ELF and plasma AUC_0-8 was 3.87 mcg·h/mL and 5.27 mcg·h/mL, respectively. The estimated ratio of ELF AUC to unbound plasma AUC is approximately 15.

Elimination

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.

The mean (min to max) elimination half-life of lefamulin is approximately 8 hours (3 to 20 h) in patients with CABP.

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.

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.

Patients with Hepatic Impairment

The disposition of lefamulin was evaluated in non-infected subjects with normal hepatic function and with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) 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. On average, unbound lefamulin plasma AUC_0-inf was increased 3-fold in subjects with severe hepatic impairment compared to that in subjects with normal hepatic function. There is no information to evaluate the effect of hepatic impairment on the disposition of lefamulin following administration of XENLETA Tablets. Thus, XENLETA Tablets are not recommended in patients with moderate or severe hepatic impairment [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].

Drug Interaction Studies

Clinical Studies

Effect of Other Drugs on the Pharmacokinetics of Lefamulin

Strong CYP3A inducers or P-gp inducers: oral rifampin (strong inducer) reduced the mean lefamulin AUC_0-inf and C_max by 28% and 8%, respectively, when administered concomitantly with XENLETA Injection. Additionally, oral rifampin reduced the mean lefamulin AUC_0-inf and C_max by 72% and 57%, respectively, when administered concomitantly with XENLETA Tablets.

Strong CYP3A inhibitors or P-gp inhibitors: oral ketoconazole (strong inhibitor) increased the mean lefamulin AUC_0-inf and C_max by 31% and 6%, respectively, when administered concomitantly with XENLETA Injection. Additionally, oral ketoconazole (strong inhibitor) increased the lefamulin AUC_0-inf and C_max by 165% and 58%, respectively, when administered concomitantly with XENLETA tablets.

Effect of Lefamulin on the Pharmacokinetics of Other Drugs

CYP3A Substrates: No clinically significant differences in the pharmacokinetics of midazolam were observed when administered concomitantly with XENLETA Injection. Mean AUC_0-inf and C_max of midazolam were increased by approximately 200% and 100%, respectively, when oral midazolam (CYP3A substrate) was administered concomitantly with and at 2 or 4 hours after administration of XENLETA Tablets.

P-gp substrates: No clinically significant differences in the pharmacokinetics of digoxin (P-gp substrate) were observed when administered concomitantly with XENLETA Tablets.

In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically

Lefamulin inhibited CYP2C8 (IC₅₀=37.0 mcg/mL), BCRP (Breast Cancer Resistance Protein) (IC₅₀=21.4 mcg/mL), and MATE1 (IC₅₀=0.15 mcg/mL).

12.4 Microbiology

Mechanism of Action

XENLETA is a systemic pleuromutilin antibacterial. It inhibits bacterial protein synthesis through interactions (hydrogen bonds, hydrophobic interactions, and Van der Waals forces) with the A- and P-sites of the peptidyl transferase center (PTC) in domain V of the 23s rRNA of the 50S subunit. The binding pocket of the bacterial ribosome closes around the mutilin core for an induced fit that prevents correct positioning of tRNA.

XENLETA is bactericidal in vitro against S. pneumoniae, H. influenzae and M. pneumoniae (including macrolide-resistant strains), and bacteriostatic against S. aureus and S. pyogenes at clinically relevant concentrations.

XENLETA is not active against Enterobacteriaceae and Pseudomonas aeruginosa.

Resistance

The resistance frequency to XENLETA due to spontaneous mutations in vitro at 2-8 times the MIC was 2 x 10^-9 to <2 x 10^-11 for S. aureus, <1 x 10^-9 to <3 x 10^-10 for S. pneumoniae, and <4 x 10^-9 to <2 x 10^-10 for S. pyogenes. Resistance development at sub-MIC concentrations required greater than 1 mutational step with no resistant clones detected at ≥4-times MIC.

Resistance mechanisms that affect XENLETA include specific protection or modification of the ribosomal target by ABC-F proteins such as vga (A, B, E), lsa(E), sal(A), Cfr methyl transferase, or by mutations of ribosomal proteins L3 and L4. Cfr methyl transferase has the potential to mediate cross-resistance between lefamulin and phenicols, lincosamides, oxazolidinones, and streptogramin A antibacterials.

Some isolates resistant to β-lactams, glycopeptides, macrolides, mupirocin, quinolones, tetracyclines, and trimethoprim-sulfamethoxazole may be susceptible to XENLETA.

Interaction with Other Antimicrobials

In vitro studies demonstrated no antagonism between XENLETA and other antibacterial drugs (e.g., amikacin, azithromycin, aztreonam, ceftriaxone, levofloxacin, linezolid, meropenem, penicillin, tigecycline, trimethoprim/sulfamethoxazole, and vancomycin).

XENLETA has demonstrated synergy in vitro with doxycycline against S. aureus.

Antimicrobial Activity

XENLETA has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1.1)]:

Gram-positive Bacteria

Streptococcus pneumoniae

Staphylococcus aureus (methicillin-susceptible isolates)

Gram-negative Bacteria

Haemophilus influenzae

Other Bacteria

Mycoplasma pneumoniae

Chlamydophila pneumoniae

Legionella pneumophila

At least 90% of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoints for XENLETA against isolates of similar genus or organism group. However, the safety and efficacy of XENLETA in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.

Gram-positive Bacteria

Staphylococcus aureus (methicillin-resistant [MRSA] isolates)

Streptococcus agalactiae

Streptococcus anginosus

Streptococcus mitis

Streptococcus pyogenes

Streptococcus salivarius

Gram-negative Bacteria

Haemophilus parainfluenzae

Moraxella catarrhalis

Susceptibility Test Methods

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.