Xenleta is indicated for the treatment of community-acquired pneumonia (CAP) in adults when it is considered inappropriate to use antibacterial agents that are commonly recommended for the initial treatment of CAP or when these have failed (see section 5.1). Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Posology The recommended dosage of Xenleta is described in Table 1. Patients may be treated throughout with intravenous lefamulin according to their clinical condition. Patients who commence treatment by the intravenous route may be switched to the oral tablets (see the Summary of Product Characteristics for Xenleta 600 mg tablets) when clinically indicated. Table 1: Dosage of Xenleta Dosage Treatment duration Intravenous lefamulin only: 150 mg of Xenleta every 12 hours by intravenous infusion over 60 minutes 7 days Intravenous lefamulin with option to switch to oral lefamulin: 7 days total treatment by the intravenous or combined intravenous and oral routes Dosage Treatment duration 150 mg of Xenleta every 12 hours by intravenous infusion over 60 minutes with option to switch to 600 mg Xenleta tablet orally every 12 hours Special populations Elderly No dosage adjustment is required for the elderly (see section 5.2). Renal impairment No dosage adjustment is required in renally impaired patients, including those receiving haemodialysis (see sections 4.4 and 5.2). Hepatic impairment No dosage adjustment is required in patients with hepatic impairment (see sections 4.4 and 5.2). Paediatric population The safety and efficacy of lefamulin in children and adolescents less than 18 years of age have not yet been established. No data are available. Method of administration Intravenous use. Xenleta is administered by intravenous infusion over 60 minutes in an infusion volume of 250 mL. The recommended infusion rate should not be exceeded. For instructions on dilution of the medicinal product before administration, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Hypersensitivity to any other members of the pleuromutilin class. Coadministration with moderate or strong inducers of CYP3A (e.g. efavirenz, phenytoin, rifampicin) (see section 4.5). Coadministration with CYP3A substrates (e.g. antipsychotics, erythromycin, tricyclic antidepressants) that prolong the QT interval (see section 4.5). Coadministration with medicinal products that prolong the QT interval such as Class IA (e.g. quinidine, procainamide) or Class III (e.g. amiodarone, sotalol) antiarrhythmic medicinal products (see section 4.5). Known QT prolongation. Electrolyte disturbances, particularly uncorrected hypokalemia. Clinically relevant bradycardia, unstable congestive heart failure, or history of symptomatic ventricular arrhythmias. Coadministration with sensitive CYP2C8 substrates (e.g. repaglinide) (see section 4.5).

Prolongation of QTc interval and potential QTc-interval prolongation-related clinical conditions Changes in cardiac electrophysiology have been observed in nonclinical and clinical studies with lefamulin. In clinical trials in patients with community-acquired pneumonia, the mean change in QTcF from baseline to Day 3 to 4 was 11.4 msec. Post-baseline QTcF increases >30 msec and >60msec were seen in 17.9% and in 1.7% of patients, respectively, and were more frequent following intravenous lefamulin dosing compared to oral dosing. The magnitude of QT prolongation may increase with increasing concentrations of lefamulin or increasing the rate of infusion of the intravenous formulation. Therefore, the recommended dose and infusion rate should not be exceeded. Lefamulin should be used with caution in patients with renal failure who require dialysis because metabolic disturbances associated with renal failure may lead to QT prolongation. Lefamulin should be used with caution in patients with mild, moderate, or severe cirrhosis because metabolic disturbances associated with hepatic insufficiency may lead to QT prolongation. Clostridioides (formerly known as Clostridium) difficile- associated diarrhoea C. difficile associated diarrhoea (CDAD) has been reported with lefamulin and may range in severity from mild diarrhoea to fatal colitis. CDAD must be considered in all patients who present with diarrhoea during or subsequent to the administration of lefamulin (see section 4.8). Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial medicinal products. If CDAD is suspected or confirmed, ongoing antibacterial medicinal product use not directed against C. difficile may need to be discontinued. Appropriate supportive measures together with the administration of specific treatment for Clostridioides difficile should be considered. Non-susceptible microorganisms Prolonged use may result in the overgrowth of non-susceptible organisms which may require interruption of treatment or other appropriate measures. Effects on hepatic transaminases Monitoring of hepatic transaminases (ALT, AST) is recommended during treatment, especially in patients whose transaminases are elevated at baseline (see section 4.8). Hepatic impairment Patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment have reduced lefamulin protein binding compared to healthy subjects or subjects with mild (Child-Pugh Class A) hepatic impairment. Treatment should be initiated in patients with moderate or severe hepatic impairment only after a careful benefit/risk evaluation, due to possible adverse reactions related to higher free concentrations of lefamulin, including prolongation of the QTcF interval. Patients should be monitored closely during treatment. Excipients This medicinal product contains 1,055 mg sodium per dose, equivalent to 52.75% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Pharmacodynamic

Women of childbearing potential Women of childbearing potential should use effective contraception during treatment with Xenleta. Women taking oral contraceptives should use an additional barrier method of contraception. Pregnancy There are no data from the use of lefamulin in pregnant women. Studies in animals have shown increased incidence of stillbirth (see section 5.3). Animal studies are insufficient with respect to embryo-foetal development (see section 5.3). Xenleta is not recommended during pregnancy. Breast-feeding It is unknown whether lefamulin/metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of lefamulin/metabolites in milk (see section 5.3). A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Xenleta. Fertility The effects of lefamulin on fertility in humans have not been studied. Lefamulin caused no impairment of fertility or reproductive performance in rats (see section 5.3).

Xenleta has no influence on the ability to drive and use machines.

Summary of the safety profile The most frequently reported adverse reactions are administration site reactions (7%), diarrhoea (7%), nausea (4%), vomiting (2%), hepatic enzyme elevation (2%), headache (1%), hypokalaemia (1%), and insomnia (1%). Administration site reactions apply to intravenous administration and led to treatment discontinuation in <1%. Gastrointestinal disorders were predominantly associated with the oral formulation of lefamulin and led to treatment discontinuation in <1%. The most frequently reported serious adverse reaction is atrial fibrillation (<1%). Tabulated list of adverse reactions Based on pooled data from Phase 3 trials for both intravenous and oral formulations, the following adverse reactions have been identified with lefamulin. Adverse reactions are classified according to System Organ Class and frequency. Frequency categories are defined as: very common (=1/10), common (=1/100 to <1/10), uncommon (=1/1,000 to <1/100), rare (=1/10,000 to <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from the available data). Table 3: Frequency of adverse reactions by system organ class from clinical trials System organ class Common Uncommon Infections and infestations Clostridioides difficile colitis Oropharyngeal candidiasis Vulvovaginal mycotic infection Blood and lymphatic system disorders Anaemia Thrombocytopenia Metabolism and nutrition disorders Hypokalaemia Psychiatric disorders Insomnia Anxiety Nervous system disorders Headache Dizziness Somnolence Cardiac disorders Electrocardiogram QT prolonged Atrial fibrillation Palpitations Respiratory, thoracic and mediastinal disorders Oropharyngeal pain Gastrointestinal disorders Diarrhoea Nausea Vomiting Abdominal pain Abdominal pain upper Constipation Dyspepsia Epigastric discomfort Gastritis Gastritis erosive Hepatobiliary disorders Alanine aminotransferase increased* Aspartate aminotransferase increased* Alkaline phosphatase increased Gamma- glutamyltransferase increased Renal and urinary disorders Urinary retention General disorders and administration site conditions Infusion site pain Infusion site phlebitis Infusion site erythema Infusion site bruising Infusion site coldness Investigations Creatinine phosphokinase increased *In Phase 3 trials (pooled data for intravenous and oral formulations), post-baseline alanine aminotransferase values >3x and >5x ULN occurred in 5% and 2% of Xenleta patients compared with 5% and 1% of moxifloxacin patients. Post-baseline aspartate aminotransferase values >3x and >5x ULN occurred in 4% and 1% of Xenleta patients compared with 2% and 1% of moxifloxacin patients. Those affected were asymptomatic with reversible clinical laboratory findings that typically peaked within the first week of Xenleta dosing. No Xenleta patient met Hy’s Law criteria. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

The highest single doses of lefamulin administered in clinical trials were 400 mg intravenous in healthy subjects which were not associated with any serious adverse reactions. The QT interval may increase with increasing exposure to lefamulin. Treatment of with lefamulin should consist of observation and general support measures. Haemodialysis will not significantly remove lefamulin from the systemic circulation.

Pharmacotherapeutic group: antibacterials for systemic use, pleuromutilins, ATC code: J01XX12. Mechanism of action Lefamulin is a pleuromutilin antibacterial agent. It inhibits bacterial protein synthesis by interacting with the A- and P- sites of the peptidyl transferase centre (PTC) in the central part of domain V of the 23S rRNA of the 50S ribosomal subunit, preventing correct positioning of the tRNA. Resistance Resistance to lefamulin in normally susceptible species may be due to mechanisms that include specific protection or modification of the ribosomal target by ABC-F proteins such as vga (A, B, E), Cfr methyl transferase, or by mutations of ribosomal proteins L3 and L4 or in domain V of 23S rRNA. Cfr generally confers cross-resistance with oxazolidinones, lincosamides, phenicols and group A streptogramins. ABC-F proteins can confer cross-resistance with lincosamides and group A streptogramins. Organisms resistant to other pleuromutilin class antibacterial agents are generally cross-resistant to lefamulin. The activity of lefamulin is not affected by mechanisms that confer resistance to beta- lactams, macrolides, quinolones, tetracyclines, folate-pathway inhibitors, mupirocin and glycopeptides. Inherent resistance to lefamulin occurs in Enterobacterales (e.g. Klebsiella pneumoniae) and non- fermenting Gram-negative aerobes (e.g. Pseudomonas aeruginosa, Acinetobacter baumannii). Antibacterial activity in combination with other antibacterial agents In vitro studies demonstrated no antagonism between lefamulin and amikacin, azithromycin, aztreonam, ceftriaxone, levofloxacin, linezolid, meropenem, penicillin, tigecycline, trimethoprim/sulfamethoxazole, and vancomycin). Susceptibility testing interpretive criteria The Minimum Inhibitory Concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) recommended interpretive criteria are: Minimum Inhibitory Concentrations (mg/L) Organism Susceptible (=S) Resistant (>R) Streptococcus pneumoniae 0.5 0.5 Staphylococcus aureus 0.25 0.25 PK/PD relationship The antimicrobial activity of lefamulin against S. pneumoniae and S. aureus correlated best with the ratio of the area under the concentration-time curve of free drug over 24 hours to the minimum inhibitory concentration (24-h AUC/MIC ratio). Clinical efficacy against specific pathogens Efficacy has been demonstrated in clinical studies against pathogens susceptible to lefamulin in vitro listed under each indication: Community-acquired Pneumonia • Gram-positive bacteria: - Streptococcus pneumoniae - Staphylococcus aureus • Gram-negative bacteria: - Haemophilus influenzae - Legionella pneumophila • Other bacteria: - Mycoplasma pneumoniae - Chlamydophila pneumoniae Clinical efficacy has not been established against the following pathogens that are relevant to the approved indications although in vitro studies suggest that they would be susceptible to lefamulin in the absence of acquired mechanisms of resistance: • Gram-negative bacteria: - Haemophilus parainfluenzae - Moraxella catarrhalis Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with Xenleta in one or more subsets of the paediatric population in community-acquired pneumonia (see section 4.2 for information on paediatric use). Information from clinical trials In a post-hoc, subgroup analysis from two Phase 3 trials in patients with community- acquired pneumonia, the clinical cure rates at a post-treatment visit in patients with any of a positive sputum culture, positive blood culture or positive urinary antigen test for S. pneumoniae were lower for patients treated with lefamulin compared to patients treated with moxifloxacin. When treatment commenced by the intravenous route the cure rates were 28/36 [77.8%; (95% confidence intervals (CIs) 60.8% to 89.9%)] for lefamulin vs. 26/31 [83.9%; (95% CI 66.3% to 94.6%)] for moxifloxacin. When treatment commenced by the oral route, the cure rates were 19/25 (76%; 95% CI 55.9% to 90.6%) vs. 30/32 (93.8%; 95% CI 79.2% to 99.2%), respectively.

Absorption Not applicable. Distribution Lefamulin is moderate to highly bound to plasma proteins (alpha-1 acid glycoprotein > human serum albumin) within a range of 88-97% at a concentration of 1 µg/mL, 83-94% at 3 µg/mL, and 73-86% at 10 µg/mL (depending on assay), demonstrating saturable, non-linear binding. The steady-state volume of distribution (Vss) is approximately 2.5 L/kg. Rapid tissue distribution of lefamulin into skin and soft tissues was demonstrated using microdialysis, and into the epithelial lining fluid (ELF) using bronchoalveolar lavage. Biotransformation In plasma, between 24 and 42% of lefamulin is metabolised primarily by CYP3A phase I reactions, leading mainly to hydroxylated metabolites devoid of antibacterial properties, most notably the main metabolite BC-8041 (2R-hydroxy lefamulin). BC- 8041 is the only metabolite in plasma accounting for >10% (13.6% to 17.3%) of total drug related material after oral dosing while no metabolites exceeded 10% (=6.7%) after intravenous dosing. Elimination Elimination was multiphasic and the terminal t1/2 ranged between 9-10h after a single oral or intravenous administration. Overall, lefamulin was primarily eliminated via the non-renal route. Between 9.6%-14.1% of an intravenous dose of lefamulin was excreted as unchanged drug in the urine. The total body clearance and the renal clearance following 150mg intravenous infusion were approximately 20L/h and 1.6L/h, respectively. Special populations No clinically significant differences in the pharmacokinetics of lefamulin were observed based on gender, race or weight. Elderly In CAP patients there was a trend of increasing lefamulin exposure with increasing age, with a~50% increase in AUC0-24 at steady-state in patients aged =85 years compared to patients aged <65 years. Renal impairment A study was conducted to compare lefamulin pharmacokinetics following intravenous administration of 150 mg in 8 subjects with severe renal impairment and 7 matched healthy control subjects. Another 8 subjects requiring haemodialysis received 150 mg lefamulin intravenously immediately before dialysis (on-dialysis) and on a non- dialysis day (off-dialysis). The AUC, Cmax, and CL of lefamulin and its main metabolite were comparable between subjects with severe renal impairment and matched healthy subjects, and in subjects requiring haemodialysis whether on- or off- dialysis. Lefamulin and its main metabolite were not dialyzable. Renal impairment did not impact lefamulin elimination. Hepatic impairment A study was conducted to compare lefamulin pharmacokinetics following intravenous administration of 150 mg in 8 subjects with moderate hepatic impairment (Child- Pugh Class B), 8 subjects with severe hepatic impairment (Child-Pugh Class C), and 11 matched healthy control subjects. No clinically meaningful changes in the total AUC, Cmax, and CL of lefamulin and its main metabolite were observed between subjects with moderate or severe hepatic impairment and matched healthy control subjects. Hepatic impairment did not meaningfully impact lefamulin elimination. Plasma protein binding decreased with increased impairment.

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, and genotoxicity. In rats, there were no effects on male or female fertility that were considered related to lefamulin. Lefamulin/metabolites are excreted into the milk of lactating rats. Maximal concentrations of radioactivity in plasma and milk were 3.29 and 10.7 µg equivalents/g, respectively, following a single dose of 30 mg/kg radio-labelled lefamulin. Lefamulin/metabolites crossed the placenta in pregnant rats. In the plasma of suckling rat pups, lefamulin exposure was demonstrated in only 1 of 3 litters of treated dams in each of the mid and high dose groups on post-natal day 4. No test item was quantified in pup’s plasma on post-natal day 20. Adverse reactions seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows: In the rat embryo-foetal development study of lefamulin during organogenesis (GD 6- 17), there were 1, 0, 2, and 1 malformed foetuses in control, low, mid, and high dose groups. Findings included malformations (cleft palate, short lower jaw, vertebral and rib malformations, and a cyst in the neck region) at the mid and high doses, but the relationship to treatment is considered equivocal. Decreased or no ossification in a number of skeletal elements in all treated groups may indicate treatment-related developmental delay at all doses evaluated. In the rabbit embryo-foetal development study of lefamulin during organogenesis (GD 6-18), low numbers of live foetuses in utero in treated groups limited the interpretation of the study. Additional findings in the high dose group included decreased foetal weight and decreased or no ossification of skeletal elements, which may be indicative of developmental delay. In a prenatal and postnatal development study in rats the pup live birth index was reduced (87.4%) in the high dose group. In the absence of related findings at the same dose level in the rat embryo-foetal development study, stillbirth was considered to be a late stage pregnancy or delivery effect. Evidence of dose-dependent regenerative anaemia in both species indicated lefamulin was potentially haemolytic at concentrations that are ten times higher than the concentration of the infusion solution which will be used clinically. This effect was not apparent from an in vitro evaluation of blood compatibility using human blood at a concentration of 0.6 mg/mL.

Concentrate Sodium chloride Water for injections Solvent Citric acid Sodium citrate Sodium chloride Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

4 years. After dilution The chemical and physical in-use stability of the diluted solution has been demonstrated for 24 hours at room temperature and 48 hours at 2°C to 8°C. From a microbiological point of view the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

Concentrate Store in a refrigerator (2°C to 8°C). Do not freeze. Solvent Store below 25°C. Do not freeze. For storage conditions after dilution of the medicinal product, see section 6.3.

One pack contains: Type I glass, closed with a stopper (chlorobutyl rubber) and sealed with a flip off cap, 2 vials with 15 mL concentrate. Polypropylene (PP) infusion bags, 2 bags with 250 mL solvent.

General precautions Each vial and infusion bag are for single use only. Standard aseptic techniques should be used for solution preparation and administration. Instructions for dilution and infusion Xenleta concentrate must be mixed into the bag of solvent containing 250 mL solution of 10mM citrate buffered saline and administered by infusion. 1. Aseptically withdraw 15 mL of Xenleta from the concentrate vial. 2. Transfer concentrate to the bag of solvent containing 250 mL solution of 10mM citrate buffered 0.9% sodium chloride injection. 3. Discard any unused portion from the concentrate vial. The vial of concentrate and the bag of solvent solution is single-use only. 4. The diluted solution should be clear and colourless. Parenteral medicinal products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 5. Administer by intravenous infusion over a period of 60 minutes by direct infusion or through a Y-type intravenous infusion set which may already be in place. Avoid rapid or bolus intravenous infusion. 6. Administer by intravenous infusion only. The compatibility of reconstituted Xenleta with intravenous medicinal products, additives, or substances other than 10mM citrate buffered 0.9% sodium chloride intravenous infusion and 0.9% sodium chloride intravenous infusion has not been established. If a common intravenous line is being used to administer other medicinal products in addition to Xenleta, the line should be flushed before and after each Xenleta administration with 0.9% sodium chloride intravenous infusion. Disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

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