来法莫林(Xenleta)中文说明书

Lefamulin, developed by Nabriva Therapeutics, is a new antibacterial drug.

Indications for Xenleta

For the treatment of community-acquired bacterial pneumonia caused by susceptible bacteria, including: Streptococcus pneumoniae, methicillin-sensitive [oxacillin-sensitive] strains of Staphylococcus aureus, Haemophilus influenzae, Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydia pneumoniae.

Lefamoren (Xenleta) usage and dosage

1. Oral administration

Take oral tablets on an empty stomach (i.e. at least 1 hour before a meal or at least 2 hours after a meal). Swallow tablets whole with 6-8 ounces of water; do not cut, chew, or crush.

2. Dosage

600 mg every 12 hours for 5 days.

3. Prescription limit

The maximum dose is 600 mg every 12 hours for 5 days.

4. Special groups

(1), patients with hepatic insufficiency

Mild hepatic insufficiency (Child-Pugh A grade): No dose adjustment is required. Moderate or severe hepatic insufficiency (Child-Pugh class B or C): Not recommended; no pharmacokinetic studies have been conducted, and adverse reactions need to be monitored.

(2), Patients with renal insufficiency

Mild, moderate or severe renal insufficiency, including patients receiving hemodialysis: No dose adjustment is required.

(3) Elderly patients

No specific dosage recommendations.

5. Treatment of missed doses

If you miss a dose of famolin and you remember it within 4 hours after the scheduled dose, you should take it as soon as possible and take the next dose at the original time.

If you miss a dose and do not remember it until more than 4 hours after the scheduled time, skip the dose and take the next dose at the originally scheduled time.

The pictures come from public channels (such as the official website of the FDA, the official website of the original drug manufacturer, etc.) and are for reference only.

Contraindications of Xenleta

1. Known allergy to Xenleta, other pleuromutilin antibiotics or any ingredients in the preparation.

2. It is prohibited to use oral lefamoren at the same time as sensitive CYP3A4 substrates (such as pimozide) that can prolong the QT interval.

Lefamoren (Xenleta) Precautions

1. QT interval prolongation

Avoid using lefamorelin in patients with known QT interval prolongation or ventricular arrhythmias (including torsade de pointes). If lefamulin cannot be avoided in such patients, the electrocardiogram should be monitored.

Concomitant use of Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic drugs or other drugs that prolong the QT interval (e.g., erythromycin, pimozide, moxifloxacin, antipsychotics, tricyclic antidepressants) may increase the risk of QT prolongation; avoid concurrent use with these drugs. If concurrent use cannot be avoided, electrocardiograms should be monitored.

Patients with mild, moderate, or severe hepatic impairment and patients with renal failure requiring dialysis may be at increased risk for QT prolongation because metabolic disorders associated with hepatic and renal insufficiency may lead to QT prolongation. If lefamulin cannot be avoided in such patients, the electrocardiogram should be monitored.

2. Fetal/neonatal morbidity and mortality

According to animal research results, use by pregnant women may cause harm to the fetus. It has been shown to be embryo-fetal toxic, lethal and teratogenic in animals.

For women of childbearing potential, a pregnancy test should be performed before starting treatment with famolin; pregnancy should be avoided during drug treatment.

3. Superinfection/Clostridium difficile-associated diarrhea and colitis

If diarrhea occurs during or after treatment, the possibility of Clostridium difficile-associated diarrhea should be considered and treated accordingly. A careful history should be taken because C. difficile -associated diarrhea may occur 2 months or later after the end of anti-infective therapy.

If C. difficile -associated diarrhea is suspected or confirmed, anti-infective drugs that are not specific to C. difficile should be discontinued if possible. Initiate appropriate anti-infectious therapy for C. difficile (e.g., fidaxomicin, vancomycin, metronidazole), supportive care (e.g., fluid and electrolyte management, protein supplementation), and undergo surgical evaluation as clinically indicated.

4. Selection and use of anti-infective drugs

In order to reduce the occurrence of drug-resistant bacteria and maintain the effectiveness of lefamoren and other antibacterial drugs, they should only be used to treat infections that are confirmed or strongly suspected to be caused by sensitive bacteria.

Information about FDA-recognized test methods, quality control standards, and specific interpretation standards for in vitro susceptibility testing of antimicrobial drugs is available at [website].

Lefamorelin (Xenleta) Use in Special Populations

1. Pregnancy

There are no data on the use of lefamorelin in pregnant women to assess the drug-related risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Based on animal studies, use by pregnant women may cause harm to the fetus.

If a pregnant woman accidentally takes lefamorelin or becomes pregnant while taking the drug, her exposure to lefamorelin should be reported to the Lefamorelin Pregnancy Pharmacovigilance Program.

2. Lactation period

It is unclear whether lefamoren will be distributed into human milk, affect milk secretion or affect nursing infants. In rats, lefamoren is distributed into breast milk.

Due to the potential risk of serious adverse reactions (e.g., QT interval prolongation) in nursing infants, women should not breastfeed while taking Lefamolin and within 2 days after the last dose.

3. Women of childbearing potential

For women of childbearing potential, a pregnancy test should be performed before starting famolin treatment.

It is recommended that females of childbearing potential use effective contraception during treatment with Lefamolin and within 2 days after the last dose.

4. Pediatric use

The safety and effectiveness in patients under 18 years of age have not been established.

5. Elderly use

In clinical studies evaluating Lefamolin, 41.5% of patients were ≥65 years old. No overall differences in safety or effectiveness were observed between these older patients and younger adults.

6. Hepatic insufficiency

Metabolic disorders related to hepatic insufficiency may lead to prolongation of the QT interval. Patients with hepatic insufficiency should monitor their electrocardiogram during treatment with oral or intravenous famolin.

It is not recommended for use in patients with moderate or severe hepatic impairment. The pharmacokinetics of oral lefamoren have not been studied in patients with hepatic impairment.

7. Renal insufficiency

Metabolic disorders associated with renal failure requiring dialysis may lead to prolongation of the QT interval. Such patients should have their electrocardiogram monitored during treatment with lefamorelin; renal insufficiency does not affect the pharmacokinetics of lefamorelin.

Common adverse reactions of lefamoren (Xenleta)

Mainly include diarrhea, nausea, vomiting, elevated liver enzymes, etc.

Lefamoren (Xenleta) drug interactions

1. Drugs affecting liver microsomal enzymes

(1), moderate and strong inhibitors of CYP3A: If combined with oral lefamorelin, there may be a pharmacokinetic interaction (increased lefamorelin exposure) and may increase the risk of toxicity.

(2) Moderate and strong inducers of CYP3A: If combined with lefamorelin, there may be a pharmacokinetic interaction (reducing lefamorelin exposure) and possible reduction in efficacy.

2. Drugs metabolized by hepatic microsomal enzymes

CYP3A substrates: There may be pharmacokinetic interactions with lefamoren, which may increase the exposure of CYP3A substrates and may increase the risk of adverse reactions.

3. Drugs that affect or are affected by membrane transport proteins

(1) P-glycoprotein inhibitors: If combined with oral lefamorelin, there may be a pharmacokinetic interaction (increased lefamorelin exposure) and may increase the risk of toxicity.

(2) P-glycoprotein inducers: There may be pharmacokinetic interactions (reducing lefamoren exposure) and may reduce efficacy.

4. Drugs that prolong the QT interval

There may be pharmacological interactions (increasing the risk of QT interval prolongation). Avoid simultaneous use with other drugs known to prolong the QT interval.

Xenleta pharmacokinetics

1. Absorption

The absolute bioavailability after tablet administration is approximately 25%. The peak time is 0.88-2 hours after administration. The AUC increased proportionally above the dose in the single oral dose range of 500-750 mg.

In healthy adults, systemic exposure after a single 600 mg oral dose (in the fasted state) was similar to that after a single 150 mg intravenous dose. In patients with CABP, mean lefamorelin AUC and peak concentrations were 73% and 30% higher, respectively, than those reported in healthy individuals.

Food effects: Compared with the fasting state, a single 600 mg oral dose taken with a high-fat, high-calorie meal reduced peak concentration and AUC by 23% and 18%, respectively.

2. Distribution

Distribution range: The average steady-state distribution volume after intravenous administration is approximately 86 liters, indicating widespread tissue distribution.

Plasma protein binding rate: 95%–97%.

3. Metabolism

Mainly metabolized through CYP3A4.

4. Elimination pathway

About 89% of the dose is eliminated in feces (8-25% is the original drug), and 5% is eliminated in the urine (the original drug and metabolites).

Half-life: approximately 8 hours in CABP patients (range: 3-20 hours).

Pharmacokinetics of Xenleta in special populations

1. Severe hepatic insufficiency

Compared with those with normal liver function, the half-life is extended (17.5 hours vs. 11.5 hours).

2. Renal insufficiency (including those receiving hemodialysis)

There is no clinically important difference in pharmacokinetics.

Mechanism of action of Xenleta

Xenleta selectively inhibits the protein synthesis of susceptible bacteria by interacting with the A and P positions of the peptidyl transferase center of the 50S subunit of bacterial ribosomes, thereby preventing the correct positioning of tRNA, inhibiting peptidyl transfer, blocking P position interactions and preventing the normal formation of active 50S ribosomal subunits.

Active against certain Gram-positive bacteria (including Streptococcus pneumoniae and methicillin-susceptible strains of Staphylococcus aureus) and certain Gram-negative bacteria (including Haemophilus influenzae and Legionella pneumophila) in vitro and in clinical infections. It is also active against Mycoplasma pneumoniae (including macrolide-resistant strains) and Chlamydia pneumoniae in vitro and in clinical infections.

Although active in vitro against methicillin-resistant Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus, Streptococcus mitis, Streptococcus salivarius, Haemophilus parainfluenzae, and Moraxella catarrhalis, safety and efficacy for the treatment of clinical infections caused by these bacteria have not been established.

Not active against Enterococcus faecalis, Enterobacteriaceae, Acinetobacter baumannii or Pseudomonas aeruginosa.

The incidence of spontaneous mutations that reduce sensitivity or resistance to lefamulin is low.

Resistance mechanisms that may affect susceptibility to lefamoren include modifications or mutations in certain ribosomal target proteins, including Cfr methyltransferase, which may mediate cross-resistance with other anti-infective drugs with overlapping interaction sites (e.g., oxazolidinones, lincosamides, phenylpropanols, streptogramins). However, the potential for cross-resistance between lefamulin and other anti-infective drugs appears to be low.

Lefamoren (Xenleta) storage

Oral tablets: 20°C–25°C (can be exposed to 15°C–30°C).