Lefamulin Acetate

XENLETA is a pleuromutilin antibacterial indicated for the treatment of adults with community-acquired bacterial pneumonia (CABP) caused by susceptible microorganisms. ( 1.1 ) 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 bacteria. ( 1.2 )

1.1 Community-Acquired Bacterial Pneumonia (CABP) 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 .

1.2 Usage 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. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

XENLETA Injection Clear, colorless solution in a single-dose clear glass vial. Each vial contains 150 mg of lefamulin in 15 mL of 0.9% sodium chloride for further dilution [see Dosage and Administration ( 2.4 )] . XENLETA Tablets Blue, oval, film-coated tablet with ‘LEF 600’ printed in black on one side. Each tablet contains 600 mg of lefamulin. Injection A single-dose clear glass vial containing 150 mg of lefamulin in 15 mL of 0.9% sodium chloride for further dilution prior to intravenous infusion. ( 3 ) Tablets 600 mg of lefamulin. ( 3 )

XENLETA is contraindicated in patients with known hypersensitivity to lefamulin, pleuromutilin class drugs, or any of the components of XENLETA. ( 4.1 ) Concomitant use of XENLETA tablets with CYP3A substrates that prolong the QT interval is contraindicated. ( 4.2 )

4.1 Hypersensitivity XENLETA is contraindicated in patients with known hypersensitivity to lefamulin, pleuromutilin class drugs, or any of the components of XENLETA. 4.2 CYP3A4 Substrates That Prolong the QT Interval XENLETA Tablets are contraindicated with sensitive CYP3A4 substrates that prolong the QT interval (for example, pimozide). Concomitant administration of oral XENLETA with sensitive CYP3A4 substrates may result in increased plasma concentrations of these drugs, leading to QT prolongation and cases of torsades de pointes [see Warnings and Precautions ( 5.1 ), Drug Interactions ( 7.2 ), and Clinical Pharmacology ( 12.3 )] .

QT Prolongation : Avoid use in patients with known QT prolongation, ventricular arrhythmias including torsades de pointes, and patients receiving drugs that prolong the QT interval such as antiarrhythmic agents. ( 5.1 ) Embryo-Fetal Toxicity : May cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. ( 5.2 , 8.1 , 8.3 ) Clostridioides difficile -associated Diarrhea (CDAD) : Evaluate patients who develop diarrhea. ( 5.3 ) 5.1 QT Prolongation XENLETA has the potential to prolong the QT interval of the electrocardiogram (ECG) in some patients. Avoid XENLETA use in the following patients: Patients with known prolongation of the QT interval Patients with ventricular arrhythmias including torsades de pointes Patients receiving Class IA (for example, quinidine, procainamide) or Class III (for example, amiodarone, sotalol) antiarrhythmic agents Patients receiving other drugs that prolong the QT interval, such as antipsychotics, erythromycin, pimozide, moxifloxacin, and tricyclic antidepressants In patients with renal failure who require dialysis, metabolic disturbances associated with renal failure may lead to QT prolongation. In patients with mild, moderate, or severe hepatic impairment, metabolic disturbances associated with hepatic impairment may lead to QT prolongation. If use with XENLETA cannot be avoided in specific populations predisposed to QT prolongation or those receiving another drug that prolongs the QT interval, ECG monitoring is recommended during treatment. The magnitude of QT prolongation may increase with increasing concentrations of XENLETA or increasing the rate of infusion of the intravenous formulation. Therefore, the recommended dose and infusion rate should not be exceeded.

5.2 Embryo-Fetal Toxicity Based on findings from animal studies, lefamulin may cause fetal harm when administered to pregnant women. Animal studies indicate that administration of lefamulin resulted in an increased incidence of post-implantation fetal loss and stillbirths in rats and rabbits treated during the period of organogenesis or in rats treated from the beginning of organogenesis through the time of weaning. Additional rat pup deaths were observed during early lactation that were likely related to maternal treatment with lefamulin. Decreased fetal body weights and ossification in rats and rabbits, and apparent delay in sexual maturation in rats may indicate treatment-related developmental delay, while other findings such as malformations in rats at systemic exposures lower than the systemic exposure in CABP patients may indicate a risk for embryo-fetal toxicity. Verify pregnancy status in females of reproductive potential prior to initiating XENLETA. Advise females of reproductive potential to use effective contraception during treatment with XENLETA and for 2 days after the final dose. Advise pregnant women and females of reproductive potential of the potential risk to a fetus [see Use in Specific Populations ( 8.1 , 8.3 )] .

5.3 Clostridioides difficile -associated Diarrhea Clostridioides difficile -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XENLETA, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile . C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing isolates of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated.

5.4 Development of Drug-Resistant Bacteria Prescribing XENLETA in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

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 Meitheal Pharmaceuticals Inc. at 1-888-808-5529 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/m 2 . 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).

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 1-888-808-5529 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, 2 R -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.

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