Xenleta

Posology The recommended dosage of lefamulin 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.

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 Oral use. The tablets should be swallowed whole with water.

2).

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 9 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.

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. 4 msec. 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 4 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.

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).