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[150 mg ] [250 mL citrate buffer diluent bags supplied by manufacturer ] [60 minutes]
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.
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.
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).
XENLETA is a semi-synthetic antibacterial agent for oral and intravenous administration.
XENLETA, a pleuromutilin derivative, is available as 14-O-{[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin in the form of an acetic acid salt (acetate). It is a chemical substance with a molecular weight of 567.79 grams per mole.
XENLETA Injection supplied as a sterile injection for intravenous use is available as a clear colorless solution in a glass vial containing 168 mg of lefamulin acetate equivalent to 150 mg of lefamulin in 15 mL of 0.9% sodium chloride. This is equivalent to 10 mg/mL lefamulin. The inactive ingredients are sodium chloride and water for injection.
XENLETA Injection must be diluted with the diluent supplied with XENLETA Injection, before administration by intravenous infusion. Each supplied diluent infusion bag contains 250 mL of 10 mM citrate buffered (pH 5) 0.9% sodium chloride. The diluent is a clear, colorless solution. The inactive ingredients are citric acid anhydrous, sodium chloride, trisodium citrate dihydrate, and water for injection. Each 100 mL contains: sodium chloride 900 mg, trisodium citrate dihydrate 200 mg, and citric acid anhydrous 61.5 mg in water for injection. Electrolytes per 1000 mL: sodium 174 mEq; chloride 154 mEq. The osmolality is 280-340 mOsm/kg and the pH is 4.5-5.5.
XENLETA is a systemic pleuromutilin antibacterial. It inhibits bacterial protein synthesis through interactions (hydrogen bonds, hydrophobic interactions, and Van der Waals forces) with the A- and P-sites of the peptidyl transferase center (PTC) in domain V of the 23s rRNA of the 50S subunit. The binding pocket of the bacterial ribosome closes around the mutilin core for an induced fit that prevents correct positioning of tRNA.
XENLETA is bactericidal in vitro against S. pneumoniae, H. influenzae and M. pneumoniae (including macrolide-resistant strains), and bacteriostatic against S. aureus and S. pyogenes at clinically relevant concentrations.
XENLETA is not active against Enterobacteriaceae and Pseudomonas aeruginosa.
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)
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.
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.
TThe 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, efamulin 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. VVerify 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 Clostridium difficile-associated Diarrhea Clostridium ifficile-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.
IIf 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.
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.
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)].
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).
Clear, colorless solution in a single-dose clear glass vial. Each vial contains 150 mg of lefamulin in 15 mL of 0.9% sodium chloride for further dilution [see Dosage and Administration (2.4)].
How Supplied XENLETA Injection is a clear, colorless, sterile, nonpyrogenic solution for intravenous administration containing 150 mg of lefamulin in 15 mL 0.9% sodium chloride in a single-dose vial intended for dilution in 250 mL of 10 mM citrate buffered (pH 5) 0.9% sodium chloride. The drug product is provided in a clear type I glass 15 mL vial with a gray rubber stopper, aluminum seal and flip off cap. The diluent is provided in infusion bags containing 250 mL of sterile, nonpyrogenic 10 mM citrate buffered (pH 5) 0.9% sodium chloride solution. The vial stopper and infusion bag are not made with natural rubber latex.
They are supplied as follows:
150 mg single dose lefamulin vials (NDC 72000-120-06); packed in cartons of 6.
250 mL citrate buffer diluent bags (NDC 72000-030-06); packed in cartons of 6.
Storage and Handling XENLETA Injection should be stored at 2°C to 8°C (36°F to 46°F). Store in a refrigerator. Do not freeze. The diluent bags should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature] [see Dosage and Administration (2.5)].
