Lefamulin

1 INDICATIONS AND USAGE 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.

12.1 Mechanism of Action XENLETA is an antibacterial drug [see Microbiology ( 12.4 )] .

2 DOSAGE AND ADMINISTRATION For treatment of adults with CABP, the recommended dosage of XENLETA is as follows: *With the option to switch to XENLETA Tablets 600 mg every 12 hours to complete the treatment course. Dosage Treatment Duration 150 mg every 12 hours by intravenous infusion over 60 minutes* ( 2.1 ) 5 to 7 days 600 mg orally every 12 hours. ( 2.1 ) 5 days Patients with Hepatic Impairment : Reduce the dosage of XENLETA Injection to 150 mg infused over 60 minutes every 24 hours in patients with severe hepatic impairment (Child-Pugh Class C). XENLETA Tablets have not been studied in and are not recommended for patients with moderate (Child-Pugh Class B) or severe hepatic impairment ( 2.2 ). Administration Instruction for XENLETA Tablets : Take at least 1 hour before a meal or 2 hours after a meal. Swallow XENLETA Tablets whole with water (6 to 8 ounces). ( 2.3 ) Administration Instruction for XENLETA Injection : Infuse over 60 minutes. ( 2.3 ) See Full Prescribing Information for additional information on the administration and preparation of XENLETA Tablets and Injection. ( 2.4 ) 2.1 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 [see Dosage and Administration ( 2.2 )] . Table 1: Dosage of XENLETA in Adult CABP Patients *With the option to switch to XENLETA Tablets 600 mg every 12 hours to complete the treatment course. 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 2.2 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 [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )]. 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). 2.3 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 [see Dosage and Administration ( 2.4 )] . 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 [see Clinical Pharmacology ( 12.3 )]. 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. 2.4 Preparation of XENLETA Injection for Intravenous Infusion Dilute the entire 15 mL vial of XENLETA Injection into the diluent bag supplied with XENLETA injection that contains 250 mL of 10 mM citrate buffered 0.9% sodium chloride. Use aseptic technique when adding XENLETA Injection into the diluent bag. Mix thoroughly. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use the diluent bag only if the solution is clear and the container is undamaged. Do not use the diluent bag in series connections. Do not add other additives

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 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

5 WARNINGS AND PRECAUTIONS 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

4 CONTRAINDICATIONS 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 )] .

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