Xenleta

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xenleta 600 mg film-coated tablets 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains lefamulin acetate equivalent to 600 mg of lefamulin. 
 
For the full list of excipients, see section 6.1. 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
Blue, oval, film-coated tablet with ‘LEF 600’ printed in black on one side. 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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. 
 
4.2 Posology and method of administration 
 
Posology 
 
The recommended dosage of Xenleta is described in Table 1. 
Patients may be treated throughout with oral lefamulin according to their clinical condition. Patients 
who commence treatment by the intravenous route (see the Summary of Product Characteristics for 
Xenleta solution for infusion) may be switched to the oral tablets when clinically indicated. 
 
Table 1: Dosage of Xenleta 

Dosage Treatment duration 
Oral lefamulin only: 
 
600 mg Xenleta tablet orally every 12 hours 

5 days 

Intravenous lefamulin with option to switch to oral lefamulin: 
 
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  

7 days total treatment 
by the intravenous or 
combined intravenous 
and oral routes  

 
Special populations 
 
Elderly 
No dosage adjustment is required for the elderly (see section 5.2). 
 



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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  
 
Oral use. 
The tablets should be swallowed whole with water. Xenleta should be taken on an empty stomach.  
 
4.3 Contraindications 
 
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) 
or with strong inhibitors of CYP3A (e.gclarithromycin, itraconazole, ritonavir) (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).  
 
4.4 Special warnings and precautions for use 
 
Prolongation of QTc interval and potential QTc-interval prolongation-related clinical conditions 
 
Changes in cardiac electrophysiology have been observed in non-clinical 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. 
 
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. 



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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 medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-
free’. 
 
4.5 Interaction with other medicinal products and other forms of interaction  
 
Pharmacodynamic interactions 
 
Co-administration of lefamulin with other medicinal products known to prolong the QT interval is 
contraindicated (see section 4.3).  
 
Pharmacokinetic interactions 
 
Effects of other products on lefamulin 
 
Use with moderate and strong CYP3A/P-gp inducers 
Medicinal products that are moderate or strong CYP3A inducers (e.g. rifampicin, St John´s wort 
[Hypericum perforatum], carbamazepine, phenytoin, bosentan, efavirenz, primidone) could 
significantly decrease lefamulin plasma concentration and may lead to reduced therapeutic effect of 
lefamulin. Co-administration of such medicinal products with lefamulin is contraindicated (see section 
4.3).  
 



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Use with strong CYP3A/P-gp inhibitors 
Medicinal products that are strong CYP3A and P-gp inhibitors (e.g. clarithromycin, diltiazem, 
itraconazole, ketoconazole, nefazodone, posaconazole, ritonavir-containing regimens, voriconazole) 
may alter absorption of lefamulin and therefore increase lefamulin plasma concentrations. Co-
administration of such medicinal products or grapefruit juice with lefamulin is contraindicated (see 
section 4.3).  
 
Potential for lefamulin to affect other medicinal products 
 
Lefamulin is a moderate CYP3A inhibitor but has no induction potential.  
 
Co-administration of oral lefamulin with agents metabolised by CYP3A such as alprazolam, alfentanil, 
ibrutinib, lovastatin, simvastatin, , triazolam, vardenafil, and verapamil may result in increased plasma 
concentrations of these medicinal products. See Table 2. 
 
Co-administration of lefamulin with agents metabolised by CYP2C8 (e.g. repaglinide) may result in 
increased plasma concentrations of these medicinal products. Co-administration with sensitive 
substrates of CYP2C8 is contraindicated (see section 4.3 and Table 2). 
 
In a clinical drug-drug interaction study, no clinically relevant interaction was observed when 
lefamulin was co-administered with the P-gp substrate digoxin. Clinical drug interaction studies with 
lefamulin and substrates of other transporters have not been performed. In vitro studies indicated that 
lefamulin acts as an inhibitor of OATP1B1, OATP1B3, BCRP, OCT1 and MATE1 transporters. 
Therefore, caution is recommended when co-administering lefamulin with sensitive substrates of these 
transporters, especially for those substrates with a narrow therapeutic window. 
 
Table 2 summarises effects on plasma concentrations of lefamulin and on co-administered medicinal 
products expressed as least-square mean ratios (90% confidence interval). The direction of the arrow 
indicates the direction of the change in exposures (Cmax and AUC), where ↑ indicates an increase more 
than 25%, ↓ indicates a decrease more than 25%, and ↔ indicates no change (equal to or less than 
25% decrease or increase). The table below is not all inclusive. 
 
Table 2: Interactions and dose recommendations of oral Xenleta with other medicinal products 

Medicinal product 
by therapeutic 
areas/possible 
mechanism of 

interaction 

Effect on 
medicinal 

product levels 
Cmax AUC Clinical comments 

ANTIARRHYTHMICS 
Digoxin 
0.5 mg single dose 
 
(Inhibition of P-gp) 

↔ Digoxin 1.05 
(0.88-1.26) 

1.11 
(0.98-1.27) 

No dose adjustment 
required. 

ANTIDEPRESSANTS 
Fluvoxamine* 
100 mg twice daily 
 
(Mild inhibition of 
CYP3A) 

Not studied 
Expected ↔ 
Lefamulin 

  No dose adjustment 
required. 

ANTIDIABETICS 
Metformin 
1000 mg singe dose 
 
(Inhibition of  
MATE, OCT1, 
OCT2)  

Not studied 
 

  Caution is 
recommended. Co-
administration with 
lefamulin may lead to 
higher exposures of 
metformin. Patients 
should be monitored. 



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Medicinal product 
by therapeutic 
areas/possible 
mechanism of 

interaction 

Effect on 
medicinal 

product levels 
Cmax AUC Clinical comments 

Repaglinide* 
0.25 mg single dose 
 
(Inhibition of 
CYP3A4,  
CYP2C8) 

Not studied 
Expected↑ 
Repaglinide 

  Co-administration with 
lefamulin may lead to 
higher exposures of 
repaglinide and is 
contraindicated (see 
section 4.3).  

ANTIFUNGALS 
Ketoconazole  
200 mg twice daily 
 
(Strong inhibiton of 
CYP3A4) 

↑ Lefamulin  1.58 
(1.38-1.81) 

2.65 
(2.43-2.90) 

Co-administration with 
strong CYP3A 
inhibitors like 
ketoconazole may lead 
to increased exposures 
of lefamulin and is 
contraindicated (see 
section 4.3). 

Fluconazole* 
400 mg day 1 + 200 
mg once daily  
 
(Moderate 
inhibition of 
CYP3A) 

Not studied 
Expected ↑ 
Lefamulin 

  Co-administration of 
medicinal products 
known to prolong QT 
interval is 
contraindicated (see 
section 4.3). 

ANTIMYCOBACTERIALS 
Rifampicin 
600 mg once daily 
 
(Strong induction of 
CYP3A)  

↓ Lefamulin  0.43 
(0.37-0.50) 

0.28 
(0.25-0.31) 

Co-administration of 
strong CYP3A inducers 
may result in reduced 
therapeutic effect of 
lefamulin and is 
contraindicated (see 
section 4.3). 

ETHINYL-OESTRADIOL-CONTAINING PRODUCTS 
Ethinyl 
oestradiol*(EE) 
35 µg once daily 
 
(Inhibition of 
CYP3A4) 

Not studied 
 

  Use with caution. 
(see Section 4.6).  

HIV-ANTIVIRAL AGENTS 
Efavirenz * 
600 mg once daily 
 
(Moderate 
induction of 
CYP3A4) 

Not studied 
Expected ↓ 
Lefamulin 

  Co-administration of 
moderate CYP3A 
inducers may result in 
reduced therapeutic 
effect of lefamulin and 
is contraindicated (see 
section 4.3). 

BENZODIAZEPINE BZ1 RECEPTOR ANTAGONIST 
Zolpidem* 
10 mg single dose 
 
(Inhibition of 
CYP3A4) 

Not studied 
Expected ↑ 
Zolpidem 

  Monitor for adverse 
reactions during co-
administration with 
lefamulin. Consider 
dosage adjustment of 
zolpidem#. 



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Medicinal product 
by therapeutic 
areas/possible 
mechanism of 

interaction 

Effect on 
medicinal 

product levels 
Cmax AUC Clinical comments 

GASTRIC ACID SUPPRESSORS/NEUTRALIZERS 
Omeprazole  Not studied 

Expected: ↔ Lefamulin 
No dose adjustment 
required. 

HERBAL PRODUCTS 
St. John’s Wort 
 
(Strong induction of 
CYP3A4) 

Not studied 
Expected: ↓ Lefamulin 

Co-administration of 
strong CYP3A inducers 
may result in reduced 
therapeutic effect of 
lefamulin and is 
contraindicated (see 
section 4.3). 

HMG-COA REDUCTASE INHIBITORS 
Rosuvastatin 
20 mg single dose 
Atorvastatin, 
Lovastatin, 
Pravastatin 
 
(Inhibition of 
CYP3A, BCRP, 
OATP1) 

Not studied 
 

  Use with caution. 

SEDATIVE AGENTS 
Midazolam 
2 mg oral single 
dose 
 
(Inhibition of 
CYP3A4) 

↔ Midazolam 2.03 
(1.84-2.23) 

3.07 
(2.75-3.43) 

Caution is recommened. 
when co-administered 
with oral lefamulin. 
Consider dosage 
adjustment of 
midazolam#. 

*Based on in vitro interaction studies, a physiological based pharmacokinetic model was developed 
and used for prediction. 
#Refer to the respective SmPC. 
 
4.6 Fertility, pregnancy and lactation 
 
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.  



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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). 
 
4.7 Effects on ability to drive and use machines 
 
Xenleta has no influence on the ability to drive and use machines. 
 
4.8 Undesirable effects  
 
Summary of the safety profile 
 
The most frequently reported adverse reactions are diarrhoea (7%), nausea (4%), vomiting (2%), 
hepatic enzyme elevation (2%), headache (1%), hypokalaemia (1%), and insomnia (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 



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Hepatobiliary disorders Alanine aminotransferase 
increased* 
Aspartate aminotransferase 
increased*  

Alkaline phosphatase increased 
Gamma-glutamyltransferase 
increased 

Renal and urinary disorders 
 

Urinary retention 
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. 
 
4.9 Overdose 
 
The highest single doses of lefamulin administered in clinical trials were 750 mg oral in healthy 
subjects which were not associated with any serious adverse reactions. The QT interval may increase 
with increasing exposure to lefamulin. Treatment of overdose with lefamulin should consist of 
observation and general support measures. Haemodialysis will not significantly remove lefamulin 
from the systemic circulation. 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
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. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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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: 
 

Organism Minimum Inhibitory Concentrations (mg/L) 
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 

 



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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. 
 
5.2 Pharmacokinetic properties 
 
Absorption 
 
After oral administration of an immediate-release 600 mg tablet formulation, oral bioavailability of 
lefamulin under fasted conditions was 25.8%. Exposure on Day 1 (AUC0-12h) was equivalent to the 
exposure obtained with lefamulin 150 mg administered intravenously. 
 
The concomitant administration of a high-fat, high calorie breakfast with a single oral dose of 600 mg 
lefamulin (immediate release tablet) resulted in a slightly reduced absolute bioavailability (21.0%).  
 
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 between 1-10 µg/mL. 
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 9-10 h 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 150 mg intravenous infusion were 
approximately 20 L/h and 1.6 L/h, respectively.  
 
Special populations 
 
No clinically significant differences in the pharmacokinetics of lefamulin were observed based on 
gender, race, or weight.  



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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. 
 
5.3 Preclinical safety data 
 
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, respectively. 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 higher than the concentration of the infusion solution which will 



13 

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. 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
 
Mannitol (E421) 
Povidone (K30) 
Microcrystalline cellulose (E460) 
Croscarmellose sodium (E468) 
Talc 
Colloidal silicon dioxide 
Magnesium stearate 
 
Tablet coating 
 
Poly(vinyl alcohol) (partially hydrolysed) (E1203) 
Titanium dioxide 
Macrogol/PEG 
Talc 
Indigo carmine aluminum lake (E132) 
 
Tablet printing 
 
Shellac  
Black iron oxide (E172) 
Propylene glycol 
 
6.2 Incompatibilities 
 
Not applicable.  
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container  
 
One pack contains: PVC/PE/PCTFE / Aluminium blisters with 10 film-coated tablets. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 



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7. MARKETING AUTHORISATION HOLDER 
 
Nabriva Therapeutics Ireland DAC 
Alexandra House, Office 225/227 
The Sweepstakes Ballsbridge 
Dublin 4  
D04 C7H2 
Ireland 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/20/1457/002 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation:  
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
  

http://www.ema.europa.eu/


15 

 
This medicinal product is subject to additional monitoring. This will allow quick identification of 

new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xenleta 150 mg concentrate and solvent for solution for infusion 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each vial of concentrate contains lefamulin acetate equivalent to 150 mg of lefamulin in 15 mL of 
normal saline (0.9% sodium chloride), to be diluted to a final concentration of 0.6 mg/mL. 
 
Excipients with known effect 
 
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. 
 
For the full list of excipients, see section 6.1. 
 
3. PHARMACEUTICAL FORM 
 
Concentrate and solvent for solution for infusion. 
The concentrate is a colourless solution. 
The solvent is a colourless solution. 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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. 
 
4.2 Posology and method of administration 
 
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 



16 

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. 
 
4.3 Contraindications 
 
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).  
 



17 

4.4 Special warnings and precautions for use 
 
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. 
 



18 

4.5 Interaction with other medicinal products and other forms of interaction 
 
Pharmacodynamic interactions 
 
Co-administration with other medicinal products known to prolong the QT interval is contraindicated 
(see section 4.3). 
 
Pharmacokinetic interactions 
 
Effects of other products on lefamulin 
 
Use with moderate and strong CYP3A/P-gp inducers 
Medicinal products that are moderate or strong CYP3A inducers (e.g. rifampicin, St John´s wort 
[Hypericum perforatum], carbamazepine, phenytoin, bosentan, efavirenz, primidone) could 
significantly decrease lefamulin plasma concentration and may lead to reduced therapeutic effect of 
lefamulin. Co-administration of such medicinal products with lefamulin is contraindicated (see section 
4.3). 
 
Potential for lefamulin to affect other medicinal products 
 
Co-administration of lefamulin with sensitive CYP2C8 substrates such as repaglinide may result in 
increased plasma concentrations of these medicinal products. Co-administration with sensitive 
substrates of CYP2C8 is contraindicated (See section 4.3 and Table 2). 
 
In a clinical drug-drug interaction study, no clinically relevant interaction was observed when 
lefamulin was co-administered with the P-gp substrate digoxin. Clinical drug interaction studies with 
lefamulin and substrates of other transporters have not been performed. In vitro studies indicated that 
lefamulin acts as an inhibitor of OATP1B1, OATP1B3, BCRP, OCT2 and MATE1 transporters. 
Therefore, caution is recommended when co-administering lefamulin with sensitive substrates of these 
transporters, especially for those substrates with a narrow therapeutic window. 
 
Table 2 summarises effects on plasma concentrations of lefamulin and on co-administered medicinal 
products expressed as least-square mean ratios (90% confidence interval). The direction of the arrow 
indicates the direction of the change in exposures (Cmax and AUC), where ↑ indicates an increase more 
than 25%, ↓ indicates a decrease more than 25%, and ↔ indicates no change (equal to or less than 
25% decrease or increase).The table below is not all inclusive. 
 
Table 2: Interactions and dose recommendations of intravenous Xenleta with other medicinal 
products 

Medicinal product 
by therapeutic 
areas/possible 
mechanism of 

interaction 

Effect on 
medicinal 

product levels 
Cmax AUC Clinical comments 

ANTIDEPRESSANTS 
Fluvoxamine* 
100 mg twice daily 
 
(Mild inhibition of 
CYP3A) 

Not studied 
Expected ↔ 
Lefamulin 

  No dose adjustment of 
intravenous lefamulin 
required. 

ANTIDIABETICS 
Metformin 
1000 mg singe dose 
 
(Inhibition of  

Not studied 
 

  Caution is 
recommended. Co-
administration with 
lefamulin may lead to 
higher exposures of 



19 

Medicinal product 
by therapeutic 
areas/possible 
mechanism of 

interaction 

Effect on 
medicinal 

product levels 
Cmax AUC Clinical comments 

MATE, OCT1, 
OCT2)  

metformin. Patients 
should be monitored. 

Repaglinide* 
0.25 mg single dose 
 
(Inhibition of 
CYP3A4, CYP2C8) 

Not studied 
Expected 
↑Repaglinide 

  Co-administration with 
lefamulin may lead to 
higher exposures of 
repaglinide and is 
contraindicated (see 
section 4.3).  

ANTIFUNGALS 
Ketoconazole  
200 mg twice daily 
 
(Strong inhibiton of 
CYP3A4) 

↑ Lefamulin  1.06 
(0.96-1.16) 

1.26 
(1.14-1.41) 

No dose adjustment for 
intravenous lefamulin. 

Fluconazole* 
400 mg day 1 + 200 
mg once daily  
 
(Moderate 
inhibition of 
CYP3A) 

Not studied 
Expected ↔ 
Lefamulin  

  Co-administration of 
medicinal products 
known to prolong QT 
interval is 
contraindicated (see 
section 4.3). 

ANTIMYCOBACTERIALS 
Rifampicin 
600 mg once daily 
 
(Strong induction of 
CYP3A) 

↓ Lefamulin  0.92 
(0.87-0.97) 

0.73 
(0.70-0.76) 

Co-administration of 
strong CYP3A inducers 
may result in reduced 
therapeutic effect of 
lefamulin and is 
contraindicated (see 
section 4.3). 

ETHINYL-OESTRADIOL-CONTAINING PRODUCTS 
Ethinyl 
oestradiol*(EE) 
35 µg once daily 
 
(Inhibition of 
CYP3A4) 

Not studied 
Expected ↔ EE  

  Use with caution. 
(see Section 4.6).  

HIV-ANTIVIRAL AGENTS 
Efavirenz * 
600 mg once daily 
 
(Moderate 
induction of 
CYP3A4) 

Not studied 
Expected 
↓ Lefamulin 

  Co-administration of 
moderate CYP3A 
inducers may result in 
reduced therapeutic 
effect of lefamulin and 
is contraindicated (see 
section 4.3). 

BENZODIAZEPINE BZ1 RECEPTOR ANTAGONIST 
Zolpidem* 
10 mg single dose 
 
(Inhibition of 
CYP3A4) 

Not studied 
Expected  
↔ Zolpidem 

  No dose adjustment 
required. 

HERBAL PRODUCTS 



20 

Medicinal product 
by therapeutic 
areas/possible 
mechanism of 

interaction 

Effect on 
medicinal 

product levels 
Cmax AUC Clinical comments 

St. John’s Wort 
 
(Strong induction of 
CYP3A4) 

Not studied 
Expected: ↓ Lefamulin 

Co-administration of 
strong CYP3A inducers 
may result in reduced 
therapeutic effect of 
lefamulin and is 
contraindicated (see 
section 4.3). 

HMG-COA REDUCTASE INHIBITORS 
Rosuvastatin 
20 mg single dose 
Atorvastatin, 
Lovastatin, 
Provastatin 
 
(Inhibition of 
BCRP, OATP1) 

Not studied 
 

  Use with caution. 

SEDATIVE AGENTS 
Midazolam 
2 mg oral single 
dose 
 
(Inhibiton of 
CYP3A4) 

↔ Midazolam 1.03 
(0.82-1.3) 

1.17 
(0.82-1.67) 

No dose adjustment 
required when co-
administered with 
intravenous lefamulin. 

*Based on in vitro interaction studies, a physiological based pharmacokinetic model was developed 
and used for prediction. 
#Refer to the respective SmPC. 
 
4.6 Fertility, pregnancy and lactation 
 
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.  



21 

Lefamulin caused no impairment of fertility or reproductive performance in rats (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Xenleta has no influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
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 



22 

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. 
 
4.9 Overdose 
 
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 overdose with lefamulin should consist 
of observation and general support measures. Haemodialysis will not significantly remove lefamulin 
from the systemic circulation. 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
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. 
 

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23 

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: 
 

Organism Minimum Inhibitory Concentrations (mg/L) 
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). 
 



24 

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. 
 
5.2 Pharmacokinetic properties 
 
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 9-10 h 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 150 mg intravenous infusion were 
approximately 20 L/h and 1.6 L/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 



25 

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. 
 
5.3 Preclinical safety data 
 
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. 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Concentrate 
 
Sodium chloride 
Water for injections 



26 

 
Solvent 
 
Citric acid 
Sodium citrate 
Sodium chloride  
Water for injections  
 
6.2 Incompatibilities 
 
This medicinal product must not be mixed with other medicinal products except those mentioned in 
section 6.6. 
 
6.3 Shelf life 
 
3 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. 
 
6.4 Special precautions for storage 
 
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.  
 
6.5 Nature and contents of container  
 
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. 
 
6.6 Special precautions for disposal and other handling 
 
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. 



27 

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.  
 
7. MARKETING AUTHORISATION HOLDER 
 
Nabriva Therapeutics Ireland DAC 
Alexandra House, Office 225/227 
The Sweepstakes 
Ballsbridge 
Dublin 4 
D04 C7H2 
Ireland  
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/20/1457/001 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation:  
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 
 
  

http://www.ema.europa.eu/


28 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
ANNEX II 

 
A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 
  



29 

A.  MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
 
Name and address of the manufacturer responsible for batch release 
 
Nabriva Therapeutics Ireland DAC 
Alexandra House, Office 225/227 
The Sweepstakes, 
Ballsbridge 
Dublin 4  
D04 C7H2  
Republic of Ireland 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to medical prescription (see Annex I: Summary of Product Characteristics, 
section 4.2). 
 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports for this medicinal product are 
set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of 
Directive 2001/83/EC and any subsequent updates published on the European medicines web-
portal. 
 
The marketing authorisation holder shall submit the first periodic safety update report for this product 
within 6 months following authorisation. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk Management Plan (RMP) 

 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in 
the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed 
subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
 
  



30 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



31 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



32 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xenleta 600 mg film-coated tablets 
lefamulin 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains lefamulin acetate equivalent to 600 mg of lefamulin. 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
10 film-coated tablets  
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Nabriva Therapeutics Ireland DAC 
Alexandra House, Office 225/227 
The Sweepstakes, Ballsbridge 
Dublin 4, D04 C7H2 
Republic of Ireland 
 



33 

 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/20/1457/002  
 
13. BATCH NUMBER  
 
Lot  
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Xenleta 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC  
SN  
NN  
  



34 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER FOIL 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xenleta 600 mg film-coated tablets 
lefamulin 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Nabriva Therapeutics 
 
3. EXPIRY DATE 
 
EXP 
 
4. BATCH NUMBER  
 
Lot 
 
5. OTHER 
 
 
  



35 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
KIT OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xenleta 150 mg concentrate and solvent for solution for infusion 
lefamulin 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial of concentrate contains lefamulin acetate equivalent to 150 mg of lefamulin 
 
3. LIST OF EXCIPIENTS 
 
Concentrate: 
Sodium chloride 
Water for injections  
 
Solvent bag: 
Sodium chloride 
Sodium citrate 
Citric acid 
Water for injections 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate and solvent for solution for infusion 
2 vials of lefamulin concentrate 
2 solvent bags 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Intravenous use after dilution. 
For single use only.  
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 



36 

Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Nabriva Therapeutics Ireland DAC 
Alexandra House, Office 225/227 
The Sweepstakes, Ballsbridge 
Dublin 4, D04 C7H2 
Republic of Ireland 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/20/1457/001  
 
13. BATCH NUMBER  
 
Lot 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC  
SN 
NN  
 
  



37 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
VIAL CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xenleta 150 mg concentrate for solution for infusion 
lefamulin 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains lefamulin acetate equivalent to 150 mg of lefamulin. 
 
3. LIST OF EXCIPIENTS 
 
Sodium chloride 
Water for injections 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion 
 
2 vials 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Intravenous use after dilution 
For single use only. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  
Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 



38 

 
Nabriva Therapeutics Ireland DAC 
Alexandra House, Ballsbridge 
D04 C7H2, Dublin, Ireland 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/20/1457/001  
 
13. BATCH NUMBER  
 
Lot 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
 
 
  



39 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
IV Solvent for Dilution Carton 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Solvent for Xenleta 
Solvent for solution for infusion 
 
2. STATEMENT OF ACTIVE SUBSTANCE 
 
 
3. LIST OF EXCIPIENTS 
 
Sodium chloride, sodium citrate, and citric acid in water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solvent for solution for infusion 
2 bags 250 mL 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
For intravenous use. 
Single use.  
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store below 25°C.  
Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Nabriva Therapeutics Ireland DAC 
Alexandra House, Office 225/227 



40 

The Sweepstakes, Ballsbridge 
Dublin 4, D04 C7H2 
Republic of Ireland 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/20/1457/001  
 
13. BATCH NUMBER  
 
Lot 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
 
  



41 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
CONCENTRATE VIAL (15 ml) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xenleta 150 mg concentrate for solution for infusion 
lefamulin 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains lefamulin acetate equivalent to 150 mg of lefamulin 
 
3. LIST OF EXCIPIENTS 
 
Contains sodium chloride and water for injections 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Sterile concentrate  
15 mL 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use after dilution 
Single use. 
Read the package leaflet before use 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Nabriva Therapeutics Ireland DAC 



42 

Alexandra House, Ballsbridge 
D04 C7H2, Dublin, Ireland 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/20/1457/001 
 
13. BATCH NUMBER  
 
Lot 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
 
  



43 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
Label for Infusion Bag with Solvent 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Solvent for Xenleta 
IV 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
 
3. LIST OF EXCIPIENTS 
 
Each bag contains: sodium chloride, sodium citrate, and citric acid in water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solvent for solution for infusion 
250 mL 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
For intravenous use. 
Single use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store below 25°C. 
Do not freeze. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Nabriva Therapeutics Ireland DAC 
Alexandra House, Ballsbridge 



44 

D04 C7H2, Dublin, Ireland 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/20/1457/001  
 
13. BATCH NUMBER  
 
Lot 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
 
  



45 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



46 

Package leaflet: Information for the user 
 

Xenleta 600 mg film-coated tablets 
lefamulin 

 
This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 

important information for you. 
- Keep this leaflet. You may need to read it again.  
- If you have any further questions, ask your doctor, pharmacist or nurse. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.  
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Xenleta is and what it is used for 
2. What you need to know before you take Xenleta 
3. How to take Xenleta 
4. Possible side effects 
5. How to store Xenleta 
6. Contents of the pack and other information 
 
1. What Xenleta is and what it is used for 
 
Xenleta is an antibiotic medicine containing the active substance lefamulin. It belongs to a group of 
medicines called ‘pleuromutilins’. 
 
Lefamulin works by killing certain bacteria which cause infections.  
 
Xenleta is used to treat adults who have bacterial infections in the lung, also known as pneumonia, 
when other treatments for pneumonia are not considered to be suitable. 
 
2. What you need to know before you take Xenleta  
 
Do not take Xenleta 

- if you are allergic to lefamulin or any of the other ingredients of this medicine (listed in section 
6)  

- if you are allergic to other medicines from the pleuromutilin class 
- if you are taking certain medicines that might interact with Xenleta. This is because some 

medicines may stop Xenleta working or lead to side effects if they are given with Xenleta. See 
below under Other medicines and Xenleta for examples.  

- if you are taking medicines that can cause changes in the heart’s electrical activity seen with an 
ECG (see below under Other medicines and Xenleta). This is because lefamulin can cause a 
condition called QT interval prolongation i.e. abnormal electrical activity that affects the heart’s 
rhythm. 

- if you have a salt imbalance in the blood (especially low levels of potassium in the blood) 
- if you have or have had an irregular heart rhythm or an abnormal ECG finding called QT 

prolongation 
- if you have a very slow heart beat (bradycardia) 
- if your heart does not work well enough (heart failure) 

 



47 

Warnings and precautions  
Talk to your doctor, pharmacist, or nurse before you are given Xenleta 

- if you have kidney failure and require dialysis. 
- if you have cirrhosis (severe liver disease.)  

 
If any of these apply to you, or if you are not sure, tell your doctor before taking Xenleta. 
 
If you develop severe diarrhoea during or after taking Xenleta tablets, talk to your doctor because 
you may need to stop your medicine, or you may need to take another medicine to treat the diarrhoea. 
Antibiotics can lead to excessive growth of certain bacteria in your bowel (gut) that can damage the 
bowel and cause severe diarrhoea. 
 
If you develop yellow skin (jaundice) or the white of your eyes turn yellow (scleral icterus), talk 
to your doctor because you may need to stop taking Xenleta or other medicines. 
 
Other infections 
There is a small possibility that you may get a different infection caused by another bacteria during or 
after treatment with Xenleta. Your doctor will monitor you closely for any new infections and give 
you another treatment if necessary. 
 
Children and adolescents 
Xenleta is not recommended for use in children and adolescents less than 18 years old. 
 
Other medicines and Xenleta 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines, as some of them could affect or be affected by Xenleta. The lists below provide only some 
examples of medicines that should be avoided while taking lefamulin or for which caution is needed. 
Your doctor will a dvise you if lefamulin is suitable for you. 
 
You must not take any of the following medicines with lefamulin:  

- carbamazepine, phenytoin, primidone (for epilepsy)  
- efavirenz, ritonavir- (for HIV) 
- St. John’s Wort, an herbal remedy (for depression or low mood)  
- bosentan diltiazem, amiodarone, sotalol, quinidine, procainamide (for angina, high blood 

pressure or heart rhythm disturbances) 
- rifampicin, clarithromycin, erythromycin (for bacterial infections) 
- fluconazole, itraconazole, posaconazole, voriconazole (for fungal infections) 
- ketoconazole (for Cushing’s disease) 
- repaglinide (for diabetes) 
- nefazodone, amitryptylline or pimozide (for depression or other mental illness) 

 
Your doctor may need to adjust the dose of some medicines while you are taking lefamulin. These 
medicines include: 

* alprazolam, midazolam, triazolam or other drugs called benzodiazepines (for anxiety)  
* alfentanil (an opioid for pain)  
* vardenafil (for erectile dysfunction) 
* ibrutinib (for certain types of cancer) 
* lovastatin, rosuvastatin or simvastatin (to reduce cholesterol levels) 
* metformin (for diabetes) 
* zolpidem (for insomnia) 
* ethinyl oestradiol (used in birth control pills) 
* verapamil (for high blood pressure) 

 
Xenleta with food and drink  
Xenleta should be taken on an empty stomach, at least 1 hour before or 2 hours after a meal. This is 
because food and some drinks can affect the way medicines work. 



48 

 
You must not eat grapefruit or drink grapefruit juice while on treatment with Xenleta as it might 
interact with Xenleta and increase side effects.  
 
Pregnancy, breast-feeding 
Do not take Xenleta if you are pregnant or breast-feeding. If you are pregnant or breastfeeding, think 
you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before 
taking this medicine. 
 
Driving and using machines 
Taking Xenleta will not influence the ability to drive or use machines. 
 
Xenleta contains sodium 
This medicine contains less than 1 mmol sodium (23mg) per tablet, that is to say essentially, ‘sodium 
free’. 
 
3. How to take Xenleta 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. 
 
The recommended dose is one 600-mg Xenleta tablet taken every 12 hours for 5 days. The tablets 
should be swallowed whole with water. 
 
Xenleta tablets may also be taken after starting treatment with Xenleta infusion via an intravenous 
drip. The number of days you then need to take Xenleta tablets will depend on how many days you 
had treatment by a drip.  
 
Your doctor will tell you for how long you should take Xenleta. It is important that you complete the 
course. 
 
If you take more Xenleta than you should 
If you accidentally take too many tablets, contact your doctor or pharmacist.  
 
If you forget to take Xenleta 
Do not take a double dose to make up for a forgotten tablet. You should continue with your course 
from the next scheduled dose. 
 
If you stop taking Xenleta 
Take the complete course of tablets prescribed by your doctor, even if you begin to feel better before 
you have finished them all. If you stop taking the tablets too soon, the infection may return, or your 
condition may get worse. 
 
Some bacteria may remain and become resistant to antibiotics if you do not complete the course or if 
you do not take your tablets at the right time. This can result in the infection returning or in the 
antibiotic not working if the infection returns. 
 
If you get a side effect that concerns you, tell a doctor immediately to get advice before taking the next 
dose. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 



49 

Common: may affect up to 1 in 10 people 
* low potassium levels in your blood (hypokalaemia), which can cause muscle weakness, 

twitching or abnormal heart rhythm  
* difficulty sleeping (insomnia) 
* headache 
* change of the heart rhythm (seen on an ECG, which monitors the electrical activity of the heart) 
* diarrhoea 
* feeling sick (nausea) or being sick (vomiting) 
* increase of a special liver enzyme in the blood (transaminases)  
 

Uncommon: may affect up to 1 in 100 people 
* inflammation of the bowel causing diarrhoea (colitis), due to an infection by a type of bacteria 

called Clostridioides difficile (previously called Clostridium difficile) 
* fungal (yeast) infection of the throat and mouth (thrush or candida infection) 
* fungal (yeast) infection of the vagina and vulva (thrush or candida infection) 
* reduction in red blood cells (anaemia), which can make the skin pale and cause weakness or 

breathlessness  
* reduction in blood platelets (blood cells which help the blood to clot), which increases your risk 

of bleeding or bruising  
* feeling anxious 
* dizziness 
* feeling tired or drowsy 
* irregular heartbeat or rhythm or palpitations 
* pain at the back of the nose and throat 
* stomach pain, pain in the abdomen or around the stomach 
* constipation 
* indigestion, stomach acidity (heartburn), or inflammation of the stomach lining (gastritis) 
* increase of a liver enzyme in the blood (gamma-glutamyl transferase and alkaline phosphatase) 
* increase in a muscle enzyme in the blood (creatine phosphokinase) 
* difficulty in urinating or in fully emptying your bladder (urinary retention) 

 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects, you can help provide more information on the 
safety of this medicine. 
 
5. How to store Xenleta 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and blister. The expiry date 
refers to the last day of that month. 
 
This medicinal product does not require any special storage conditions 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


50 

6. Contents of the pack and other information 
 
What Xenleta contains  

- The active substance is lefamulin. Each tablet contains lefamulin acetate equivalent to 600 mg 
of lefamulin.  

- The other ingredients are colloidal silicon dioxide (E551), croscarmellose sodium (E468), 
magnesium stearate (E572), mannitol (E421), microcrystalline cellulose (E460), povidone K30, 
talc (E553b). 

- Film Coating: black iron oxide (E172), indigo carmine lake (E132), macrogol, poly (vinyl 
alcohol) (E1203), propylene glycol, shellac (E904), talc, titanium dioxide (E171). 

 
What Xenleta looks like and contents of the pack 
Xenleta 600 mg film-coated tablets are blue, oval, film-coated tablets printed with “LEF 600” in black 
on one side. 
 
Xenleta film-coated tablets are provided in blister packs of 10 tablets.  
 
Marketing Authorisation Holder and Manufacturer 
Nabriva Therapeutics Ireland DAC 
Alexandra House, Office 225/227 
The Sweepstakes, 
Ballsbridge 
Dublin 4  
D04 C7H2  
Republic of Ireland 
 
This leaflet was last revised in  
 
 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 
  



51 

 
Package leaflet: Information for the patient 

 
Xenleta 150 mg concentrate and solvent for solution for infusion 

lefamulin 
 

This medicine is subject to additional monitoring. This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you are given this medicine because it contains important 
information for you. 
- Keep this leaflet. You may need to read it again.  
- If you have any further questions, ask your doctor or nurse. 
- If you get any side effects, talk to your doctor or nurse. This includes any possible side effects 

not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Xenleta is and what it is used for 
2. What you need to know before you are given Xenleta 
3. How you will be given Xenleta 
4. Possible side effects 
5. How to store Xenleta 
6. Contents of the pack and other information 
 
1. What Xenleta is and what it is used for 
 
Xenleta is an antibiotic medicine that contains the active substance lefamulin. It belongs to a group of 
medicines called ‘pleuromutilins’. 
 
Lefamulin works by killing certain bacteria which cause infections.  
 
Xenleta is used to treat adults who have bacterial infections in the lung, also known as pneumonia, 
when other treatments for pneumonia are not considered to be suitable. 
 
2. What you need to know before you are given Xenleta 
 
You must not be given Xenleta 

- if you are allergic to lefamulin or any of the other ingredients of this medicine (listed in section 
6) 

- if you are allergic to other medicines from the pleuromutilin class 
- if you are taking certain medicines that might interact with Xenleta. This is because some 

medicines may stop Xenleta working or lead to side effects if they are given with Xenleta. See 
below under Other medicines and Xenleta for examples.  

- if you are taking medicines that can cause changes in the heart’s electrical activity seen with an 
ECG (see below under Other medicines and Xenleta). This is because lefamulin can cause a 
condition called QT interval prolongation i.e. abnormal electrical activity that affects the heart’s 
rhythm. 

- if you have a salt imbalance in the blood (especially low levels of potassium in the blood) 
- if you have or have had an irregular heart rhythm or an abnormal ECG finding called QT 

prolongation 
- if you have a very slow heart beat (bradycardia) 
- if your heart does not work well enough (heart failure) 

 



52 

Warnings and precautions  
Talk to your doctor or nurse before you are given Xenleta 

- if you have kidney failure and require dialysis. 
- if you have cirrhosis (severe liver disease) 

 
If any of these apply to you, or if you are not sure, tell your doctor before you are given Xenleta. 
 
If you develop severe diarrhoea during or after being given Xenleta, tell your doctor immediately 
since it may be necessary to interrupt your treatment. Antibiotics can lead to excessive growth of 
certain bacteria in your bowel (gut) that can damage the bowel and cause severe diarrhoea.  
 
If you develop yellow skin (jaundice) or the white of your eyes turn yellow (scleral icterus), talk 
to your doctor because you may need to stop taking Xenleta or other medicines. 
 
Other infections 
There is a small possibility that you may get a different infection caused by another bacteria during or 
after treatment with Xenleta. Your doctor will monitor you closely for any new infections and give 
you another treatment if necessary. 
 
Children and adolescents 
Xenleta is not recommended for use in children and adolescents under 18 years old. 
 
Other medicines and Xenleta 
Tell your doctor if you are taking, have recently taken or might take any other medicines, as some of 
these could affect or be affected by Xenleta. The lists below provide only some examples of medicines 
that should be avoided while taking lefamulin or for which caution is needed. Your doctor will a dvise 
you if lefamulin is suitable for you. 
 
You must not take any of the following medicines with lefamulin:  

- carbamazepine, phenytoin, primidone (for epilepsy) 
- efavirenz (for HIV) 
- St. John’s Wort, an herbal remedy (for depression or low mood) 
- bosentan, diltiazem, amiodarone, sotalol, quinidine, procainamide (for angina, high blood 

pressure or heart rhythm disturbances) 
- rifampicin, clarithromycin, erythromycin (for bacterial infections) 
- fluconazole, itraconazole, posaconazole, voriconazole (for fungal infections)  
- ketoconazole (for Cushing’s disease)  
- repaglinide (for diabetes) 
- nefazodone, amitryptylline or pimozide (for depression or other mental illness) 

 
Your doctor may need to adjust the dose of some medicines while you are taking lefamulin. These 
medicines include: 

* lovastatin, rosuvastatin or simvastatin (to reduce cholesterol levels)  
* metformin (for diabetes) 
* ethinyl oestradiol (used in birth control pills) 

 
Pregnancy, breast-feeding 
You should not be given Xenleta if you are pregnant or breast-feeding. If you are pregnant or 
breastfeeding, think you may be pregnant or are planning to have a baby, ask your doctor or nurse for 
advice before you are given this medicine.  
 
Driving and using machines 
Taking Xenleta will not influence the ability to drive or use machines. 
 



53 

Xenleta contains sodium  
This medicine contains 1,055 mg sodium (main component of cooking/table salt) in each dosage unit. 
This is equivalent to 53% of the recommeded maximum daily dietary intake of sodium for an adult. 
 
3. How you will be given Xenleta 
 
Xenleta will be given to you by a doctor or nurse.  
 
The recommended dose for adults is 150 mg every 12 hours. It will be given to you through a drip 
directly into a vein (intravenously) over a period of 1 hour.  
 
A course of treatment usually lasts for 7 days, or longer if your doctor recommends it. 
 
Your doctor may decide to switch you from having Xenleta through a drip to taking Xenleta tablets to 
complete your treatment for a total (drip and tablet) of 7 days of treatment. 
 
If you are given more Xenleta than you should receive 
Xenleta will be given to you in hospital by a doctor or nurse. It is, therefore, unlikely you will be given 
too much. Tell your doctor or nurse if you are concerned that you may have been given too much 
Xenleta. 
 
If you miss a dose of Xenleta 
Xenleta will be given to you in hospital by a doctor or nurse. It is therefore unlikely you will miss a 
dose. Tell your doctor or nurse if you are concerned that you have missed a dose.  
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Common: may affect up to 1 in 10 people 

* low potassium levels in your blood (hypokalemia), which can cause muscle weakness, twitching 
or abnormal heart rhythm 

* difficulty sleeping (insomnia) 
* headache 
* diarrhoea 
* feeling sick (nausea), or being sick (vomiting) 
* increase of a special liver enzyme in the blood (transaminases) 
* redness or swelling or pain at the site of the injection  
* alteration of the heart rhythm (seen on an ECG, which monitors the electrical activity of the 

heart) 
 
Uncommon: may affect up to 1 in 100 people 

* inflammation of the bowel causing diarrhoea (colitis), due to an infection by a type of bacteria 
called Clostridioides difficile (previously called Clostridium difficile)  

* fungal (yeast) infection of the throat and mouth (thrush or candida infection) 
* fungal (yeast) infection of the vagina and vulva (thrush or candida infection) 
* reduction in red blood cells (anaemia), which can make the skin pale and cause, weakness or 

breathlessness 
* reduction in blood platelets (blood cells which help the blood to clot), which increases risk of 

bleeding or bruising  
* feeling anxious 
* dizziness 
* feeling tired or drowsy 
* irregular heart beat or rhythm or palpitations 
* pain at the back of the nose and throat 
* stomach pain, pain in the abdomen or around the stomach  
* constipation 



54 

* indigestion, stomach acidity (heartburn), or inflammation of the stomach lining (gastritis) 
* increase of a liver enzyme in the blood (gamma-glutamyl transferase and alkaline phosphatase) 
* increase in a muscle enzyme in the blood (creatine phosphokinase) 
* difficulty urinating or in fully emptying your bladder (urinary retention) 

 
Reporting of side effects 
If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not 
listed in this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. By reporting side effects, you can help provide more information on the safety of this 
medicine. 
 
5. How to store Xenleta 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the vial label and outer carton. The 
expiry date refers to the last day of that month. 
 
Concentrate: Store in a refrigerator (2°C to 8°C ). Do not freeze. 
 
Solvent: Store below 25°C. Do not freeze. 
 
After dilution:  
The stability of the diluted solution has been demonstrated for 24 hours at room temperature and 48 
hours at 2°C to 8°C. Administer immediately after dilution. 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. 
 
The diluted solution should be clear and colourless and should not be used if it contains any particles 
or the solution is cloudy. 
 
6. Contents of the pack and other information 
 
What Xenleta contains  

- The active substance is lefamulin. Each vial contains lefamulin acetate equivalent to 150 mg of 
lefamulin. 

- The other ingredients are: citric acid (E330), sodium citrate dihydrate (E331), sodium chloride 
and water for injections.  

 
What Xenleta looks like and contents of the pack 
Xenleta is a concentrate for solution for infusion.  
 
The concentrate is a clear colourless solution in a glass vial, closed with a rubber stopper and sealed 
with a lift off cap. 
 
The solvent is a clear colourless solution in a polypropylene infusion bag. 
 
Xenleta is supplied in a pack containing 2 vials of concentrate and 2 infusion bags with solvent. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


55 

Marketing Authorisation Holder and Manufacturer 
Nabriva Therapeutics Ireland DAC 
Alexandra House, Office 225/227 
The Sweepstakes, 
Ballsbridge 
Dublin 4  
D04 C7H2  
Republic of Ireland 
 
This leaflet was last revised in  
 
 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.  
 
 
<------------------------------------------------------------------------------------------------------------------------> 
 
The following information is intended for healthcare professionals only: 
 
Instructions for dilution prior to administration 
Parenteral (intravenous) medicinal products should be inspected visually for particles or discoloration 
prior to administration. Only solutions which are clear, colourless, and free of visible particles should 
be diluted. 
 
How to prepare Xenleta for administration 
 
General precautions 
 
Each vial and infusion bag is 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.  
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 or 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. 
 



56 

Disposal 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements.  
 


	ANNEX I
	SUMMARY OF PRODUCT CHARACTERISTICS
	For the full list of excipients, see section 6.1.
	4.1 Therapeutic indications
	4.2 Posology and method of administration
	4.5 Interaction with other medicinal products and other forms of interaction
	4.7 Effects on ability to drive and use machines
	4.8 Undesirable effects
	4.9 Overdose
	5.1 Pharmacodynamic properties
	Pharmacotherapeutic group: antibacterials for systemic use, pleuromutilins, ATC code: J01XX12.
	5.2 Pharmacokinetic properties
	5.3 Preclinical safety data
	6.1 List of excipients
	6.2 Incompatibilities
	6.3 Shelf life
	6.4 Special precautions for storage
	6.5 Nature and contents of container
	6.6 Special precautions for disposal
	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.
	For the full list of excipients, see section 6.1.
	4.1 Therapeutic indications
	4.2 Posology and method of administration
	4.5 Interaction with other medicinal products and other forms of interaction
	4.6 Fertility, pregnancy and lactation
	4.7 Effects on ability to drive and use machines
	4.8 Undesirable effects
	4.9 Overdose
	5.1 Pharmacodynamic properties
	Pharmacotherapeutic group: antibacterials for systemic use, pleuromutilins, ATC code: J01XX12.
	5.2 Pharmacokinetic properties
	5.3 Preclinical safety data
	6.1 List of excipients
	6.2 Incompatibilities
	6.3 Shelf life
	6.4 Special precautions for storage
	Concentrate
	Store in a refrigerator (2 C to 8 C). Do not freeze.
	6.5 Nature and contents of container
	6.6 Special precautions for disposal and other handling
	Name and address of the manufacturer responsible for batch release
	ANNEX III
	LABELLING AND PACKAGE LEAFLET
	A. LABELLING
	1. NAME OF THE MEDICINAL PRODUCT
	2. STATEMENT OF ACTIVE SUBSTANCE(S)
	3. LIST OF EXCIPIENTS
	4. PHARMACEUTICAL FORM AND CONTENTS
	5. METHOD AND ROUTE(S) OF ADMINISTRATION
	6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN
	Keep out of the sight and reach of children.
	7. OTHER SPECIAL WARNING(S), IF NECESSARY
	8. EXPIRY DATE
	9. SPECIAL STORAGE CONDITIONS
	10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE
	11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
	12. MARKETING AUTHORISATION NUMBER(S)
	EU/1/20/1457/002
	13. BATCH NUMBER
	14. GENERAL CLASSIFICATION FOR SUPPLY
	15. INSTRUCTIONS ON USE
	1. NAME OF THE MEDICINAL PRODUCT
	2. NAME OF THE MARKETING AUTHORISATION HOLDER
	3. EXPIRY DATE
	4. BATCH NUMBER
	5. OTHER
	1. NAME OF THE MEDICINAL PRODUCT
	2. STATEMENT OF ACTIVE SUBSTANCE(S)
	3. LIST OF EXCIPIENTS
	4. PHARMACEUTICAL FORM AND CONTENTS
	5. METHOD AND ROUTE(S) OF ADMINISTRATION
	6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN
	Keep out of the sight and reach of children.
	7. OTHER SPECIAL WARNING(S), IF NECESSARY
	8. EXPIRY DATE
	9. SPECIAL STORAGE CONDITIONS
	10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE
	11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
	12. MARKETING AUTHORISATION NUMBER(S)
	EU/1/20/1457/001
	13. BATCH NUMBER
	14. GENERAL CLASSIFICATION FOR SUPPLY
	15. INSTRUCTIONS ON USE
	1. NAME OF THE MEDICINAL PRODUCT
	2. STATEMENT OF ACTIVE SUBSTANCE(S)
	3. LIST OF EXCIPIENTS
	4. PHARMACEUTICAL FORM AND CONTENTS
	5. METHOD AND ROUTE(S) OF ADMINISTRATION
	6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN
	Keep out of the sight and reach of children.
	7. OTHER SPECIAL WARNING(S), IF NECESSARY
	8. EXPIRY DATE
	9. SPECIAL STORAGE CONDITIONS
	10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE
	11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
	12. MARKETING AUTHORISATION NUMBER(S)
	EU/1/20/1457/001
	13. BATCH NUMBER
	14. GENERAL CLASSIFICATION FOR SUPPLY
	15. INSTRUCTIONS ON USE
	1. NAME OF THE MEDICINAL PRODUCT
	2. STATEMENT OF ACTIVE SUBSTANCE
	3. LIST OF EXCIPIENTS
	4. PHARMACEUTICAL FORM AND CONTENTS
	5. METHOD AND ROUTE(S) OF ADMINISTRATION
	6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN
	Keep out of the sight and reach of children.
	7. OTHER SPECIAL WARNING(S), IF NECESSARY
	8. EXPIRY DATE
	9. SPECIAL STORAGE CONDITIONS
	10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE
	11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
	12. MARKETING AUTHORISATION NUMBER(S)
	EU/1/20/1457/001
	13. BATCH NUMBER
	14. GENERAL CLASSIFICATION FOR SUPPLY
	15. INSTRUCTIONS ON USE
	1. NAME OF THE MEDICINAL PRODUCT
	2. STATEMENT OF ACTIVE SUBSTANCE(S)
	3. LIST OF EXCIPIENTS
	4. PHARMACEUTICAL FORM AND CONTENTS
	5. METHOD AND ROUTE(S) OF ADMINISTRATION
	6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN
	Keep out of the sight and reach of children
	7. OTHER SPECIAL WARNING(S), IF NECESSARY
	8. EXPIRY DATE
	9. SPECIAL STORAGE CONDITIONS
	10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE
	11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
	12. MARKETING AUTHORISATION NUMBER(S)
	EU/1/20/1457/001
	13. BATCH NUMBER
	14. GENERAL CLASSIFICATION FOR SUPPLY
	15. INSTRUCTIONS ON USE
	1. NAME OF THE MEDICINAL PRODUCT
	2. STATEMENT OF ACTIVE SUBSTANCE(S)
	3. LIST OF EXCIPIENTS
	4. PHARMACEUTICAL FORM AND CONTENTS
	5. METHOD AND ROUTE(S) OF ADMINISTRATION
	6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN
	Keep out of the sight and reach of children.
	7. OTHER SPECIAL WARNING(S), IF NECESSARY
	8. EXPIRY DATE
	9. SPECIAL STORAGE CONDITIONS
	10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE
	11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
	12. MARKETING AUTHORISATION NUMBER(S)
	EU/1/20/1457/001
	13. BATCH NUMBER
	14. GENERAL CLASSIFICATION FOR SUPPLY
	15. INSTRUCTIONS ON USE
	B. PACKAGE LEAFLET
	Package leaflet: Information for the user
	Xenleta 600 mg film-coated tablets
	Do not take Xenleta
	Warnings and precautions
	Pregnancy, breast-feeding
	Driving and using machines
	If you take more Xenleta than you should
	If you forget to take Xenleta
	If you stop taking Xenleta
	Reporting of side effects
	This leaflet was last revised in
	Package leaflet: Information for the patient
	You must not be given Xenleta
	Warnings and precautions
	Pregnancy, breast-feeding
	Driving and using machines
	Taking Xenleta will not influence the ability to drive or use machines.
	If you are given more Xenleta than you should receive
	Xenleta will be given to you in hospital by a doctor or nurse. It is, therefore, unlikely you will be given too much. Tell your doctor or nurse if you are concerned that you may have been given too much Xenleta.
	If you miss a dose of Xenleta
	Xenleta will be given to you in hospital by a doctor or nurse. It is therefore unlikely you will miss a dose. Tell your doctor or nurse if you are concerned that you have missed a dose.
	Reporting of side effects
	This leaflet was last revised in