XENLETA Concentrate and solvent for solution for infusion Ref.[114854] Active ingredients: Lefamulin

Prolongation of QTc interval and potential QTc-interval prolongation-related clinical conditions

Changes in cardiac electrophysiology have been observed in nonclinical and clinical studies with lefamulin. In clinical trials in patients with community-acquired pneumonia, the mean change in QTcF from baseline to Day 3 to 4 was 11.4 msec. Post-baseline QTcF increases >30 msec and >60msec were seen in 17.9% and in 1.7% of patients, respectively, and were more frequent following intravenous lefamulin dosing compared to oral dosing.

The magnitude of QT prolongation may increase with increasing concentrations of lefamulin or increasing the rate of infusion of the intravenous formulation. Therefore, the recommended dose and infusion rate should not be exceeded.

Lefamulin should be used with caution in patients with renal failure who require dialysis because metabolic disturbances associated with renal failure may lead to QT prolongation.

Lefamulin should be used with caution in patients with mild, moderate, or severe cirrhosis because metabolic disturbances associated with hepatic insufficiency may lead to QT prolongation.

Clostridioides (formerly known as Clostridium) difficile-associated diarrhoea

C. difficile associated diarrhoea (CDAD) has been reported with lefamulin and may range in severity from mild diarrhoea to fatal colitis. CDAD must be considered in all patients who present with diarrhoea during or subsequent to the administration of lefamulin (see section 4.8). Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial medicinal products.

If CDAD is suspected or confirmed, ongoing antibacterial medicinal product use not directed against C. difficile may need to be discontinued. Appropriate supportive measures together with the administration of specific treatment for Clostridioides difficile should be considered.

Non-susceptible microorganisms

Prolonged use may result in the overgrowth of non-susceptible organisms which may require interruption of treatment or other appropriate measures.

Effects on hepatic transaminases

Monitoring of hepatic transaminases (ALT, AST) is recommended during treatment, especially in patients whose transaminases are elevated at baseline (see section 4.8).

Hepatic impairment

Patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment have reduced lefamulin protein binding compared to healthy subjects or subjects with mild (Child-Pugh Class A) hepatic impairment. Treatment should be initiated in patients with moderate or severe hepatic impairment only after a careful benefit/risk evaluation, due to possible adverse reactions related to higher free concentrations of lefamulin, including prolongation of the QTcF interval. Patients should be monitored closely during treatment.

Excipients

This medicinal product contains 1,055 mg sodium per dose, equivalent to 52.75% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Pharmacodynamic 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 (C_max 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:

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

Women of childbearing potential

Women of childbearing potential should use effective contraception during treatment with Xenleta. Women taking oral contraceptives should use an additional barrier method of contraception.

Pregnancy

There are no data from the use of lefamulin in pregnant women. Studies in animals have shown increased incidence of stillbirth (see section 5.3). Animal studies are insufficient with respect to embryo-foetal development (see section 5.3). Xenleta is not recommended during pregnancy.

Breast-feeding

It is unknown whether lefamulin/metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of lefamulin/metabolites in milk (see section 5.3). A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Xenleta.

Fertility

The effects of lefamulin on fertility in humans have not been studied.

Lefamulin caused no impairment of fertility or reproductive performance in rats (see section 5.3).

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

Summary of the safety profile

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

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

The most frequently reported serious adverse reaction is atrial fibrillation (<1%).

Tabulated list of adverse reactions

Based on pooled data from Phase 3 trials for both intravenous and oral formulations, the following adverse reactions have been identified with lefamulin. Adverse reactions are classified according to System Organ Class and frequency. Frequency categories are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from the available data).

Table 3. Frequency of adverse reactions by system organ class from clinical trials:

^* 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.

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