Lefamulin: Formulary Considerations
June 1, 2020 4 minutes read
By Samit Patel, PharmD
Clinical Pharmacist, Hematology/Oncology, Stanford Health Care
Dr. Patel reports no financial relationships relevant to this field of study.
The Food and Drug Administration (FDA) recently approved lefamulin for the treatment of adults with community-acquired bacterial pneumonia (CABP) caused by the following organisms: Streptococcus pneumoniae, Staphylococcus aureus (methicillin-susceptible isolates), Haemophilus influenzae, Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydophila pneumoniae. It does not have activity against Enterobacteriaceae and Pseudomonas aeruginosa. Lefamulin is a pleuromutilin antibacterial that inhibits bacterial protein synthesis. Because pleuromutilin drugs have a unique mechanism, they have low cross-resistance with other classes of antibiotics.1,2
Dosage
Lefamulin can be administered orally or intravenously (IV). For IV administration, the lefamulin dose is 150 mg every 12 hours (infused over 60 minutes). Oral lefamulin is given at 600 mg every 12 hours. The medication should be administered at least one hour before a meal or two hours after a meal. The duration of therapy is a minimum of five days and varies based on disease severity and response to therapy.
There is no dose adjustment for renal impairment. For hepatic impairment, oral therapy is not recommended for moderate to severe hepatic impairment (Child-Pugh class B or C). For IV therapy, dose adjustment (to 150 mg every 24 hours) is needed for severe hepatic impairment (Child-Pugh class C). Patients with severe hepatic impairment receiving IV therapy had prolonged half-lives of the drug compared to those with normal hepatic function (17.5 h vs. 11.5 h), and reduced lefamulin protein binding. On average, unbound lefamulin plasma AUC0-inf was increased threefold in subjects with severe hepatic impairment compared to those with normal hepatic function.1
Adverse Effects
The most common adverse effects were diarrhea (12%), administration site reaction (7%), nausea (3-5%) and vomiting (3%), hepatic enzyme elevation (2-3%), hypokalemia (2%), and headache (2%).1,3,4
Drug Interactions
Lefamulin is metabolized primarily by CYP3A4. Concomitant use of lefamulin injection and lefamulin tablets should be avoided with strong and moderate CYP3A4 inducers or P-gp inducers. Concomitant use of lefamulin tablets should be avoided with strong CYP3A inhibitors or P-gp inhibitors. Patients should be monitored carefully for adverse reactions with concomitant use of lefamulin and another CPY3A substrate.1
Concomitant administration of oral lefamulin with CYP3A4 substrates is contraindicated because it may result in increased plasma concentrations of these medications, leading to QT prolongation and cases of torsades de pointes.
Contraindications/warnings/precautions
Use of lefamulin should be avoided in patients who have known QT prolongation, ventricular arrhythmias including torsades de pointes, and in those who are receiving drugs that prolong the QT interval, such as antiarrhythmic medications.1
Based on animal studies, lefamulin may cause harm to a fetus, including fetal mortality, decreased fetal body weight, and developmental delays. Females of reproductive potential should be advised about the potential risk to a fetus and to use effective contraception during use of lefamulin and up to two days after the last dose of the medication.1
Studies in animals indicate that lefamulin was concentrated in the milk of lactating rats. Because of the potential for serious adverse effects, including QT prolongation, women who are lactating should pump and discard human breast milk for the duration of treatment with lefamulin and for two days after the last dose.1 Clostridium difficile-associated diarrhea has been reported with lefamulin.1
Clinical trials/evidence summary
Lefamulin’s safety and efficacy were based on two Phase III trials, LEAP Trial 1 and 2.3,4
In the LEAP Trial 1, 276 patients were randomized to IV lefamulin and 275 patients were randomized to IV moxifloxacin with or without linezolid (both groups had the option to switch to oral therapy after at least three days). IV lefamulin demonstrated noninferiority with the end point of early clinical response at three to five days after the first dose in the intent-to-treat analysis, 87.3% with lefamulin vs. 90.2% moxifloxacin with or without linezolid.3
The LEAP Trial 2 compared oral therapy, randomizing 370 patients to lefamulin and 368 patients to moxifloxacin. Oral lefamulin demonstrated noninferiority with the end of point of early clinical response after the first dose in the intent-to-treat analysis, 90.8% in both groups.4
Comparative Cost
The cost of a five-day course of lefamulin oral therapy is $1,650 (based on a 600 mg tablet average wholesale price of $165) and IV therapy is $1,230 (based on a 150 mg vial average wholesale price of $123).
Clinical Implications
Lefamulin is a novel agent indicated for CABP. Patients can be treated with oral or IV therapy, allowing for avoidance of hospitalization or expediting discharge from the hospital. Its unique mechanism of action also may help in lowering the development of resistance.
REFERENCES
- Xenleta (lefamulin) [package insert]. Nabriva Therapeutics. King of Prussia, PA; August 2019.
- Sader HS, Biedenbach DJ, Paukner S, et al. Antimicrobial activity of the investigational pleuromutilin compound BC-3781 tested against Gram-positive organisms commonly associated with acute bacterial skin and skin structure infections. Antimicrob Agents Chemother 2012;56:1619-1623.
- File TM, Goldberg L, Das A, et al. Efficacy and safety of IV-to-oral lefamulin, a pleuromutilin antibiotic, for treatment of community-
acquired bacterial pneumonia: The Phase III Lefamulin Evaluation Against Pneumonia (LEAP 1) Trial. Clin Infect Dis 2019;69:1856-1867. - Alexander E, Goldberg L, Das AF, et al. Oral lefamulin vs moxifloxacin for early clinical response among adults with community-acquired bacterial pneumonia: The LEAP 2 randomized clinical trial. JAMA 2019; Sep 27. doi: 10.1001/jama.2019.15468. [Epub ahead of print].
The Food and Drug Administration (FDA) recently approved lefamulin for the treatment of adults with community-acquired bacterial pneumonia (CABP).
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