lefamulin acetate
Brand names: Xenleta, Citric Buffered Normal Saline
Warnings
5 WARNINGS AND PRECAUTIONS QT Prolongation : Avoid use in patients with known QT prolongation, ventricular arrhythmias including torsades de pointes, and patients receiving drugs that prolong the QT interval such as antiarrhythmic agents. ( 5.1 ) Embryo-Fetal Toxicity : May cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. ( 5.2 , 8.1 , 8.3 ) Clostridioides difficile -associated Diarrhea (CDAD) : Evaluate patients who develop diarrhea. ( 5.3 ) 5.1 QT Prolongation XENLETA has the potential to prolong the QT interval of the electrocardiogram (ECG) in some patients. Avoid XENLETA use in the following patients: Patients with known prolongation of the QT interval Patients with ventricular arrhythmias including torsades de pointes Patients receiving Class IA (for example, quinidine, procainamide) or Class III (for example, amiodarone, sotalol) antiarrhythmic agents Patients receiving other drugs that prolong the QT interval, such as antipsychotics, erythromycin, pimozide, moxifloxacin, and tricyclic antidepressants In patients with renal failure who require dialysis, metabolic disturbances associated with renal failure may lead to QT prolongation. In patients with mild, moderate, or severe hepatic impairment, metabolic disturbances associated with hepatic impairment may lead to QT prolongation. If use with XENLETA cannot be avoided in specific populations predisposed to QT prolongation or those receiving another drug that prolongs the QT interval, ECG monitoring is recommended during treatment. The magnitude of QT prolongation may increase with increasing concentrations of XENLETA or increasing the rate of infusion of the intravenous formulation. Therefore, the recommended dose and infusion rate should not be exceeded. 5.2 Embryo-Fetal Toxicity Based on findings from animal studies, lefamulin may cause fetal harm when administered to pregnant women. Animal studies indicate that administration of lefamulin resulted in an increased incidence of post-implantation fetal loss and stillbirths in rats and rabbits treated during the period of organogenesis or in rats treated from the beginning of organogenesis through the time of weaning. Additional rat pup deaths were observed during early lactation that were likely related to maternal treatment with lefamulin. Decreased fetal body weights and ossification in rats and rabbits, and apparent delay in sexual maturation in rats may indicate treatment-related developmental delay, while other findings such as malformations in rats at systemic exposures lower than the systemic exposure in CABP patients may indicate a risk for embryo-fetal toxicity. Verify pregnancy status in females of reproductive potential prior to initiating XENLETA. Advise females of reproductive potential to use effective contraception during treatment with XENLETA and for 2 days after the final dose. Advise pregnant women and females of reproductive potential of the potential risk to a fetus [see Use in Specific Populations ( 8.1 , 8.3 )] . 5.3 Clostridioides difficile -associated Diarrhea Clostridioides difficile -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XENLETA, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile . C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing isolates of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated. 5.4 Development of Drug-Resistant Bacteria Prescribing XENLETA in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
Contraindications
4 CONTRAINDICATIONS XENLETA is contraindicated in patients with known hypersensitivity to lefamulin, pleuromutilin class drugs, or any of the components of XENLETA. ( 4.1 ) Concomitant use of XENLETA tablets with CYP3A substrates that prolong the QT interval is contraindicated. ( 4.2 ) 4.1 Hypersensitivity XENLETA is contraindicated in patients with known hypersensitivity to lefamulin, pleuromutilin class drugs, or any of the components of XENLETA. 4.2 CYP3A4 Substrates That Prolong the QT Interval XENLETA Tablets are contraindicated with sensitive CYP3A4 substrates that prolong the QT interval (for example, pimozide). Concomitant administration of oral XENLETA with sensitive CYP3A4 substrates may result in increased plasma concentrations of these drugs, leading to QT prolongation and cases of torsades de pointes [see Warnings and Precautions ( 5.1 ), Drug Interactions ( 7.2 ), and Clinical Pharmacology ( 12.3 )] .
Overdose
10 OVERDOSAGE Treatment of overdose with XENLETA should consist of observation and general support measures. Lefamulin and its primary metabolite are not dialyzable.
Drug interactions
7 DRUG INTERACTIONS XENLETA Injection Strong or moderate CYP3A inducers or P-gp inducers Avoid XENLETA unless the benefit outweighs the risk. Monitor for reduced efficacy. ( 7.1 ) XENLETA Tablets Strong or moderate CYP3A inducers or P-gp inducers Avoid XENLETA unless the benefit outweighs the risk. Monitor for reduced efficacy. ( 7.1 ) Strong CYP3A inhibitors or P-gp inhibitors Avoid XENLETA. ( 7.1 ) Moderate CYP3A inhibitors or P-gp inhibitors Monitor for adverse reactions. ( 7.1 ) CYP3A substrates that prolong the QT interval Concomitant use is contraindicated. ( 4.2 , 7.2 ) Midazolam and other sensitive CYP3A substrates Monitor for adverse reactions. ( 7.2 ) 7.1 Effect of Other Drugs on XENLETA Strong and Moderate CYP3A Inducers or P-gp Inducers Concomitant use of oral or intravenous XENLETA with strong CYP3A4 inducers or P-gp inducers decreases lefamulin AUC and C max [see Clinical Pharmacology ( 12.3 )] , which may reduce the efficacy of XENLETA. Avoid concomitant use of XENLETA Injection and XENLETA Tablets with strong and moderate CYP3A4 inducers or P-gp inducers unless the benefit outweighs the risks. Strong and Moderate CYP3A Inhibitors or P-gp Inhibitors Concomitant use of XENLETA Tablets with strong CYP3A inhibitors or P-gp inhibitors increases lefamulin AUC [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of adverse reactions with XENLETA Tablets. Avoid concomitant use of XENLETA Tablets with strong CYP3A inhibitors or P-gp inhibitors. Monitor for adverse effects of XENLETA Tablets when administered concomitantly with moderate CYP3A inhibitors or P-gp inhibitors. 7.2 Effect of XENLETA on Other Drugs CYP3A4 Substrates Concomitant use of XENLETA Tablets with sensitive CYP3A4 substrates increases the AUC and C max of CYP3A4 substrates [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of toxicities associated with cardiac conduction. Concomitant use with CYP3A substrates known to prolong the QT interval is contraindicated [see Contraindications ( 4.2 )] . Concomitant use of sensitive CYP3A substrates with XENLETA Tablets requires close monitoring for adverse effects of these drugs (for example, alprazolam, diltiazem, verapamil, simvastatin, vardenafil). Concomitant use of XENLETA Injection with CYP3A4 substrates does not affect the exposure of CYP3A4 substrates. 7.3 Drugs that Prolong QT The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between XENLETA and other drugs that effect cardiac conduction is unknown. Therefore, avoid concomitant use of XENLETA Injection and XENLETA Tablets with such drugs (for example, Class IA and III antiarrhythmics, antipsychotics, erythromycin, moxifloxacin, tricyclic antidepressants).
Uses
1 INDICATIONS AND USAGE XENLETA is a pleuromutilin antibacterial indicated for the treatment of adults with community-acquired bacterial pneumonia (CABP) caused by susceptible microorganisms. ( 1.1 ) To reduce the development of drug resistant bacteria and maintain the effectiveness of XENLETA and other antibacterial drugs, XENLETA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. ( 1.2 ) 1.1 Community-Acquired Bacterial Pneumonia (CABP) XENLETA is indicated for the treatment of adults with community-acquired bacterial pneumonia (CABP) caused by the following susceptible microorganisms: Streptococcus pneumoniae , Staphylococcus aureus (methicillin-susceptible isolates), Haemophilus influenzae , Legionella pneumophila , Mycoplasma pneumoniae , and Chlamydophila pneumoniae . 1.2 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of XENLETA and other antibacterial drugs, XENLETA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
Dosage forms & strengths
2 DOSAGE AND ADMINISTRATION For treatment of adults with CABP, the recommended dosage of XENLETA is as follows: *With the option to switch to XENLETA Tablets 600 mg every 12 hours to complete the treatment course. Dosage Treatment Duration 150 mg every 12 hours by intravenous infusion over 60 minutes* ( 2.1 ) 5 to 7 days 600 mg orally every 12 hours. ( 2.1 ) 5 days Patients with Hepatic Impairment : Reduce the dosage of XENLETA Injection to 150 mg infused over 60 minutes every 24 hours in patients with severe hepatic impairment (Child-Pugh Class C). XENLETA Tablets have not been studied in and are not recommended for patients with moderate (Child-Pugh Class B) or severe hepatic impairment ( 2.2 ). Administration Instruction for XENLETA Tablets : Take at least 1 hour before a meal or 2 hours after a meal. Swallow XENLETA Tablets whole with water (6 to 8 ounces). ( 2.3 ) Administration Instruction for XENLETA Injection : Infuse over 60 minutes. ( 2.3 ) See Full Prescribing Information for additional information on the administration and preparation of XENLETA Tablets and Injection. ( 2.4 ) 2.1 Recommended Dosage For treatment of adults with CABP, the recommended dosage of XENLETA is described in Table 1 below. For patients with severe hepatic impairment, dosage adjustment is required [see Dosage and Administration ( 2.2 )] . Table 1: Dosage of XENLETA in Adult CABP Patients *With the option to switch to XENLETA Tablets 600 mg every 12 hours to complete the treatment course. Dosage Treatment Duration 150 mg every 12 hours by intravenous infusion over 60 minutes* 5 to 7 days 600 mg orally every 12 hours 5 days 2.2 Dosage Adjustment for Patients with Hepatic Impairment Monitor patients with hepatic impairment for adverse reactions associated with XENLETA Injection and Tablets throughout the treatment period [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )]. XENLETA Injection Reduce the dosage of XENLETA Injection to 150 mg infused intravenously over 60 minutes every 24 hours for patients with severe hepatic impairment (Child-Pugh Class C). No dosage adjustment of XENLETA Injection is needed for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. XENLETA Tablets XENLETA Tablets have not been studied in and are not recommended for patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment. No dosage adjustment of XENLETA Tablets is needed for patients with mild hepatic impairment (Child-Pugh Class A). 2.3 Important Administration Instructions XENLETA Injection Administer XENLETA Injection by intravenous infusion over 60 minutes. Must dilute in a 250 mL solution of 10 mM citrate buffered 0.9% sodium chloride for injection supplied with XENLETA Injection before use [see Dosage and Administration ( 2.4 )] . XENLETA Tablets Take XENLETA Tablets at least 1 hour before a meal or 2 hours after a meal. Swallow XENLETA Tablets whole with water (6 to 8 ounces). Do not crush or divide XENLETA Tablets [see Clinical Pharmacology ( 12.3 )]. Missed Dose If a dose is missed, the patient should take the dose as soon as possible and anytime up to 8 hours prior to the next scheduled dose. If less than 8 hours remain before the next scheduled dose, do not take the missed dose, and resume dosing at the next scheduled dose. 2.4 Preparation of XENLETA Injection for Intravenous Infusion Dilute the entire 15 mL vial of XENLETA Injection into the diluent bag supplied with XENLETA injection that contains 250 mL of 10 mM citrate buffered 0.9% sodium chloride. Use aseptic technique when adding XENLETA Injection into the diluent bag. Mix thoroughly. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use the diluent bag only if the solution is clear and the container is undamaged. Do not use the diluent bag in series connections. Do not add other additives to the diluent bag because their compatibilities with XENLETA Injection have not been established. 2.5 Storage of XENLETA Injection After Dilution After dilution, XENLETA Injection can be stored for up to 24 hours at room temperature and up to 48 hours when refrigerated at 2°C to 8°C (36°F to 46°F).