XENLETA

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.

2). 2). 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. 6.

Summary of the safety profile The most frequently reported adverse reactions are administration site reactions (7%), diarrhoea (7%), nausea (4%), vomiting (2%), hepatic enzyme elevation (2%), headache (1%), hypokalaemia (1%), and insomnia (1%).

Administration site reactions apply to intravenous administration and led to treatment discontinuation in <1%. Gastrointestinal disorders were predominantly associated with the oral formulation of lefamulin and led to treatment discontinuation in <1%.

The most frequently reported serious adverse reaction is atrial fibrillation (<1%). Tabulated list of adverse reactions Based on pooled data from Phase 3 trials for both intravenous and oral formulations, the following adverse reactions have been identified with lefamulin.

Adverse reactions are classified according to System Organ Class and frequency. Frequency categories are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from the available data).

Table 3:

Frequency of adverse reactions by system organ class from clinical trials System organ class Common Uncommon Infections and infestations Clostridioides difficile colitis Oropharyngeal candidiasis Vulvovaginal mycotic infection Blood and lymphatic system disorders Anaemia Thrombocytopenia Metabolism and nutrition disorders Hypokalaemia Psychiatric disorders Insomnia Anxiety Nervous system disorders Headache Dizziness Somnolence Cardiac disorders Electrocardiogram QT prolonged Atrial fibrillation Palpitations Respiratory, thoracic and mediastinal disorders Oropharyngeal pain Gastrointestinal disorders Diarrhoea Nausea Vomiting Abdominal pain Abdominal pain upper Constipation Dyspepsia Epigastric discomfort Gastritis Gastritis erosive Hepatobiliary disorders Alanine aminotransferase increased* Aspartate aminotransferase increased* Alkaline phosphatase increased Gamma- glutamyltransferase increased Renal and urinary disorders Urinary retention General disorders and administration site conditions Infusion site pain Infusion site phlebitis Infusion site erythema Infusion site bruising Infusion site coldness Investigations Creatinine phosphokinase increased *In Phase 3 trials (pooled data for intravenous and oral formulations), post-baseline alanine aminotransferase values >3x and >5x ULN occurred in 5% and 2% of Xenleta patients compared with 5% and 1% of moxifloxacin patients.

Post-baseline aspartate aminotransferase values >3x and >5x ULN occurred in 4% and 1% of Xenleta patients compared with 2% and 1% of moxifloxacin patients. Those affected were asymptomatic with reversible clinical laboratory findings that typically peaked within the first week of Xenleta dosing.

No Xenleta patient met Hy’s Law criteria. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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. 4 msec. 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. 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. 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. 75% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

1. Hypersensitivity to any other members of the pleuromutilin class. g. 5). g. 5). g. g. 5). Known QT prolongation. Electrolyte disturbances, particularly uncorrected hypokalemia. Clinically relevant bradycardia, unstable congestive heart failure, or history of symptomatic ventricular arrhythmias.

g. 5).