Lefamulin

Abstract

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Generic Name: Lefamulin

Proprietary Name: Xenleta (Nabriva Therapeutics US, Inc)

Approval Rating: 1P

Therapeutic Class: Antibiotics, Pleuromutilins

Similar Drugs: Retapamulin

Sound- or Look-Alike Names: Leflunomide, Xenical

Indications

Lefamulin 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 Staphylococcus aureus [MSSA] isolates), Haemophilus influenzae, Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydophila pneumoniae. ¹

Lefamulin is also undergoing evaluation for use in the treatment of health care–acquired bacterial pneumonia/ventilator-associated bacterial pneumonia, osteomyelitis, prosthetic joint infections, acute bacterial skin and skin structure infections, and sexually transmitted diseases.^2,3

Clinical Pharmacology

Lefamulin, a pleuromutilin derivative, is a semisynthetic antibacterial agent for oral and intravenous (IV) administration that inhibits bacterial protein synthesis by selectively binding to the peptidyl transferase center of the 50S subunit of the bacterial ribosome, preventing correct positioning of the 3′ CCA ends of tRNAs (transfer ribonucleic acids) for peptide transfer.^1,4,5

Lefamulin’s in vitro antibacterial profile includes a broad spectrum of common bacterial pathogens causing respiratory tract, sexually transmitted, and skin and skin structure infections. The antibacterial spectrum comprises the gram-positive bacteria S pneumoniae, S aureus (including methicillin-resistant Staphylococcus aureus [MRSA] and community-acquired MRSA), Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus anginosus, Streptococcus mitis, Streptococcus salivarius, and Enterococcus faecium (including vancomycin-resistant enterococci); the gram-negative bacteria H influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, and Neisseria gonorrhoeae; and the atypical pathogens L pneumophila, C pneumoniae, Chlamydia trachomatis, Mycoplasma genitalium, and M pneumoniae.^1,5-12 Lefamulin 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. It is not active against Enterobacteriaceae and Pseudomonas aeruginosa.^1,12

In cross-resistance studies, lefamulin remained active against some clinical isolates resistant to macrolides, tetracyclines, beta-lactams, quinolones, sulfamethoxazole/trimethoprim, mupirocin, and glycopeptides.^1,11 Resistance due to spontaneous mutations has been observed infrequently. Resistance mechanisms affecting lefamulin include specific protection or modification of the ribosomal target by ABC-F proteins, Cfr methyltransferase, or mutations of ribosomal proteins L3 and L4.^1,13 Cfr methyltransferase has the potential to mediate cross-resistance between lefamulin and phenicols, lincosamides, oxazolidinones, and streptogramin A antibacterials. ¹

In vitro, lefamulin has demonstrated synergy with doxycycline against S aureus. No antagonism was observed between lefamulin and other antibacterials (eg, amikacin, azithromycin, aztreonam, ceftriaxone, levofloxacin, linezolid, meropenem, penicillin, tigecycline, sulfamethoxazole/trimethoprim, vancomycin).^1,14

Pharmacokinetics

Mean pharmacokinetic parameters observed after lefamulin single doses of 150 mg IV and 600 mg orally in the fasted state were comparable.^1,15 Mean oral bioavailability of lefamulin is approximately 25%, and peak plasma concentration (C_max) occurred 0.88 to 2 hours after administration to healthy participants. ¹ Bioequivalence was not established between oral lefamulin in the fed state and IV or oral administration in the fasted state; exposure was reduced and time to peak concentration was prolonged (median, 4.5 hours) when administered with food.^1,15,16 Coadministration of a single oral dose of lefamulin 600 mg with a high-fat (approximately 50% of total calories from fat), high-calorie (approximately 800-1000 calories) breakfast slightly reduced bioavailability. The mean relative reduction for oral lefamulin (fasted vs fed) was on average 22.9% (90% confidence interval [CI], 12.2%-32.3%) for C_max and 18.43% (90% CI, 11.7%-24.7%) for area under the curve (AUC_0-∞). Following a single IV dose, the AUC of lefamulin increased approximately dose proportionally, whereas C_max increased less than dose proportionally over a dose range of 25 to 400 mg. Following a single oral dose, lefamulin AUC increased more than dose proportionally over a dose range of 500 to 750 mg. Mean lefamulin AUC_0-24h and C_max were 73% and 30% higher, respectively, in patients with CABP compared with healthy participants. ¹ The pharmacokinetics of oral and IV lefamulin in patients with CABP are summarized in Table 1. ¹

Table 1.

Pharmacokinetics of Single or Multiple Doses ^a of Lefamulin in Patients With Community-Acquired Bacterial Pneumonia. ¹

Parameter	Route	Mean value after single dose	Mean value at steady state
Cmax, mcg/mL	IV	3.5	3.6
	Oral	2.24	2.24
Cmin, mcg/mL	IV	0.398	0.573
	Oral	0.593	0.765
AUC0-24h, mcg h/mL	IV	27	28.6
	Oral	30.7	32.7

Note. IV = intravenous; AUC = area under the curve.

^a150 mg IV infused over 60 minutes (every 12 hours for multiple dosing); 600 mg orally 1 hour before or 2 hours after a meal (every 12 hours for multiple dosing).

Mean plasma protein binding of lefamulin ranges from 94.8% at 2.35 mcg/mL to 97.1% at 0.25 mcg/mL in healthy adults. ¹ The mean steady-state volume of the distribution of lefamulin is 86.1 L (range, 34.2-153 L) in patients with CABP after IV administration of lefamulin. Following single IV administration of lefamulin 150 mg to healthy participants, the highest lefamulin epithelial lining fluid (ELF) concentrations were observed at the end of infusion. Mean ELF and plasma AUC_0-8 were 3.87 and 5.27 mcg h/mL, respectively. Following a single IV administration, the estimated ratio of ELF AUC to unbound plasma AUC is approximately 15. ¹

Mean total body clearance of lefamulin is 11.9 L/h (range, 2.94-30 L/h) in patients with CABP after IV administration. Mean elimination half-life of lefamulin is approximately 8 hours (range, 3-20 hours) in patients with CABP. ¹

Lefamulin is primarily metabolized by CYP3A4. In healthy adult participants administered radiolabeled lefamulin IV and oral doses, the mean total radioactivity excreted in feces was 77.3% (4.2%-9.1% unchanged) and 88.5% (7.8%-24.8% unchanged), respectively, and mean total radioactivity excreted in urine was 15.5% (9.6%-14.1% unchanged) and 5.3% (percentage unchanged not determined), respectively. ¹

Pharmacokinetics did not differ based on age, sex, race, weight, or renal impairment, including patients undergoing hemodialysis. ¹ Lefamulin pharmacokinetics have been evaluated in noninfected participants with normal hepatic function and with moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment following administration of the injection form. Following IV administration, half-life was prolonged in participants with severe hepatic impairment compared with participants with normal hepatic function (17.5 vs 11.5 hours). Protein binding of lefamulin was also reduced in participants with hepatic impairment, resulting in unbound active lefamulin concentrations that increased with the degree of hepatic impairment. Unbound lefamulin plasma AUC_0-∞ was increased 3-fold in participants with severe hepatic impairment compared with participants with normal hepatic function. The effects on lefamulin pharmacokinetics following oral administration in participants with hepatic impairment have not been assessed; the oral formulation is not recommended in patients with moderate or severe hepatic impairment. ¹

Comparative Efficacy

Indication: Community-Acquired Pneumonia

Guidelines

• Guideline: Diagnosis and treatment of adults with community-acquired pneumonia: An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America

• Reference: American Thoracic Society/Infectious Diseases Society of America ¹⁷

• Comments: For healthy outpatient adults with community-acquired pneumonia without comorbidities (eg, chronic heart, lung, liver, or renal disease; diabetes mellitus; alcoholism; malignancy; asplenia) or risk factors for antibiotic-resistant pathogens (MRSA, P aeruginosa), treatment with amoxicillin, doxycycline, or a macrolide (azithromycin, clarithromycin, clarithromycin extended release) is recommended; macrolide therapy should be considered only in areas with less than 25% pneumococcal resistance to macrolides. For outpatient adults with comorbidities, the guidelines recommend combination therapy with amoxicillin/clavulanate or cephalosporin plus a macrolide (azithromycin, clarithromycin) or doxycycline, or monotherapy with a respiratory fluoroquinolone (levofloxacin, moxifloxacin, gemifloxacin). Treatment strategies for inpatients with community-acquired pneumonia are based on severity and risk for drug resistance. For inpatient adults with nonsevere community-acquired pneumonia without risk factors for resistance, combination therapy with a beta-lactam and macrolide (ampicillin/sulbactam, cefotaxime, ceftriaxone, or ceftaroline plus azithromycin or clarithromycin) or monotherapy with a respiratory fluoroquinolone (levofloxacin, moxifloxacin) is recommended; if contraindications to both macrolides and fluoroquinolones exist, combination therapy with a beta-lactam and doxycycline is an option. For inpatients with severe community-acquired pneumonia without risk factors for resistance, a beta-lactam plus a macrolide or a beta-lactam plus a fluoroquinolone is recommended. The guidelines note that further research is needed regarding the use of newer agents, including lefamulin, for the treatment of community-acquired pneumonia in adults.

Studies

• Drug: Lefamulin vs Moxifloxacin

• Reference: File TM, et al, 2019 (LEAP 1 trial)^1,18,19

• Study Design: Phase 3, randomized, double-blind, double-dummy, active-controlled, parallel-group, multicenter, noninferiority study

• Study Funding: Nabriva Therapeutics

• Patients: 551 patients (at least 18 years of age) with acute CABP, with radiographic findings suggestive of pneumonia, Pneumonia Outcomes Research Team (PORT) risk class of at least III, and at least 3 of 4 symptoms consistent with the disease (new or increased cough, purulent sputum production, chest pain, dyspnea). Exclusion criteria were receipt of more than 1 dose of a short-acting oral or IV antibacterial for CABP within 72 hours before randomization; need for concomitant systemic antibacterial therapy potentially effective against CABP pathogens; hospitalization for 2 or more days within 90 days before symptom onset, or residence in a nursing home or long-term health care facility within 30 days before symptom onset; confirmed or suspected CABP caused by a pathogen resistant to any of the study drugs or attributable to etiologies other than community-acquired bacterial pathogens; noninfectious cause of pulmonary infiltrates; confirmed or suspected pleural empyema; or need for mechanical ventilation. Patients were mostly male (60%) and white (87%). Median patient age was 62 years (range, 19-91 years); more patients in the lefamulin group were 65 years or older (47.8% vs 39.3%) and 75 years or older (21% vs 15.3%). Approximately 53% of patients had creatinine clearance (CrCl) less than 90 mL/min. Approximately 72% of patients were classified as PORT risk class III and 28% as PORT risk class IV or V. Common comorbid conditions included hypertension (41%), asthma or chronic obstructive pulmonary disease (COPD; 17%), and diabetes mellitus (13%). The most common pathogens at baseline were S pneumoniae, H influenzae, M catarrhalis, M pneumoniae, L pneumophila, and C pneumoniae.

• Intervention: Patients were randomized (1:1) to receive lefamulin 150 mg IV every 12 hours (n = 276) or moxifloxacin 400 mg every 24 hours (n = 275). Moxifloxacin-treated patients received alternating doses of a placebo to maintain blinding. After 3 days (6 doses), patients could be switched to oral study drug if prespecified improvement criteria were met (lefamulin 600 mg every 12 hours or moxifloxacin 400 mg every 24 hours). If MRSA was suspected at screening, patients in the moxifloxacin group received adjunctive linezolid and patients in the lefamulin group received linezolid placebo. Treatment duration ranged from 5 to 10 days. In the initial protocol, patients with CABP due to MRSA or L pneumophila and patients with S pneumoniae with bacteremia received 10 days of active treatment, whereas all other lefamulin-treated patients received 5 days of active therapy and all other moxifloxacin-treated patients received 7 days of active therapy. After a protocol amendment, therapy duration changed to 7 days for both lefamulin- and moxifloxacin-treated patients, except for patients with MRSA who received 10 days of active therapy. The median duration of IV treatment was 7 days in the lefamulin group and 6 days in the moxifloxacin group, and the median duration of oral therapy was 4 days in both groups. A switch from IV to oral therapy occurred in 38.1% of lefamulin-treated patients and in 44.3% of moxifloxacin-treated patients.

Results

Primary End Point(s)

• Rate of early clinical response (ECR; defined as an improvement in 2 or more CABP signs/symptoms, no worsening in any signs/symptoms, and no use of a concomitant, nonstudy antibiotic for CABP) in the intention-to-treat (ITT) population at 96 (±24) hours after the first study drug dose (Food and Drug Administration [FDA]-required end point): 87.3% of patients with lefamulin compared with 90.2% with moxifloxacin (treatment difference, −2.9% [95% CI, −8.5%-2.8%]); noninferiority of lefamulin was demonstrated.

• Rate of investigator assessment of clinical response (IACR; defined as the resolution or improvement of CABP such that no additional antibiotic therapy was administered for CABP) at test of cure (5-10 days after the last dose of the study drug) in the modified intention-to-treat (mITT) and clinically evaluable (CE) populations (European Medicines Agency [EMA] coprimary end point):

  • mITT population: 81.7% of patients treated with lefamulin compared with 84.2% treated with moxifloxacin (treatment difference, −2.6% [95% CI, −8.9%-3.9%]); noninferiority of lefamulin was demonstrated.
  • CE population: 86.9% of patients treated with lefamulin compared with 89.4% treated with moxifloxacin (treatment difference, −2.5% [95% CI, −8.4%-3.4%]); noninferiority of lefamulin was demonstrated.

Secondary End Point(s)

• Response (ECR) and success (IACR) by baseline pathogen in the microbiological ITT population did not differ substantially between the treatment groups, but comparisons were limited by small numbers of patients in the subgroups by pathogen. The ECR ranged from 84.2% (M pneumoniae) to 100% (S aureus) for lefamulin and from 85.7% (L pneumophila) to 100% (M catarrhalis) for moxifloxacin. The IACR ranged from 72.7% (C pneumoniae) to 84.9% (S pneumoniae) for lefamulin and from 68.4% (C pneumoniae) to 100% (M catarrhalis) for moxifloxacin.

Other End Point(s)

• The most common treatment-emergent adverse events were hypokalemia, nausea, insomnia, and infusion-site pain in the lefamulin group (each in 2.9% of patients) and diarrhea in the moxifloxacin group (7.7%). Rates of study drug discontinuation due to treatment-emergent adverse events were 2.9% for lefamulin and 4.4% for moxifloxacin.

• Comments: Most patients were enrolled in Eastern Europe (79%); less than 1% were enrolled in North America. Baseline pathogens were similar between the 2 groups. Noninferiority of lefamulin was concluded if the lower limit of the 2-sided 95% CI for the treatment difference in ECR responder rates was greater than −12.5% and if the lower limit of the 2-sided 95% CI for the treatment difference in IACR success rates was greater than −10% for both the mITT and CE populations. The ECR and IACR rates by PORT risk class did not differ between the lefamulin and moxifloxacin treatment groups. The subpopulation analysis suggested that moxifloxacin was more effective than lefamulin in patients younger than 65 years based on rates of both ECR (93.4% with moxifloxacin vs 84.7% with lefamulin) and IACR (88% vs 75.9%), as well as in patients with minor disease severity according to American Thoracic Society criteria (93.8% vs 75.9% for ECR and 89.6% vs 62.3% for IACR); in patients younger than 65 years, response rates were significantly lower with lefamulin than with moxifloxacin in the presence of minor disease severity compared with those not meeting criteria for minor disease severity.

• Limitations: This study included a small number of patients with severe disease (PORT risk class V); enrollment from North America, Western Europe, and Latin America was low, precluding a sensitivity analysis by geographic region.

• Reference: Alexander E, et al, 2019 (LEAP 2 trial)^1,20-22

• Study Design: Phase 3, randomized, double-blind, double-dummy, multicenter, noninferiority study

• Study Funding: Nabriva Therapeutics

• Patients: 738 patients (at least 18 years of age) with CABP and at least 3 of 4 symptoms consistent with the disease (dyspnea, new or increased cough, purulent sputum production, chest pain) and a PORT risk class of II to IV. Exclusion criteria were receipt of more than 1 dose of a short-acting oral or IV antibacterial for CABP within 72 hours before randomization; hospitalization for 2 or more days within the past 90 days; confirmed or suspected MRSA; risk of major cardiac events or dysfunction; significant hepatic, immunologic, or hematologic diseases; or severe renal impairment (estimated CrCl less than 30 mL/min). Patients were mostly white (74%), and 52% were male. Median patient age was 59 years (range, 19-97 years); approximately 16% were 75 years or older. Approximately 50% had CrCl of less than 90 mL/min. Approximately 50% of patients were classified as PORT risk class II and 49% as PORT risk class III or IV. Common comorbid conditions included hypertension (36%), asthma or COPD (16%), and diabetes mellitus (13%).

• Intervention: Patients were randomized (1:1) to receive lefamulin 600 mg orally every 12 hours for 5 days (n = 370) or moxifloxacin 400 mg orally every 24 hours for 7 days (n = 368).

• Results: The same FDA- and EMA-defined primary end points from Leap 1 were evaluated.

Primary End Point(s)

• Rate of ECR in the ITT population at 96 (±24) hours after the first dose of the study drug: 90.8% of patients with lefamulin compared with 90.8% with moxifloxacin (treatment difference, 0.1% [95% CI, −4.4%-4.5%]); noninferiority of lefamulin was demonstrated.

• Rate of IACR at test of cure (5-10 days after the last dose) in mITT and CE populations:

  • mITT population: 87.5% of patients with lefamulin and 89.1% with moxifloxacin (treatment difference, −1.6% [95% CI, −6.3%-3.1%]).
  • CE population: 89.7% of patients with lefamulin and 93.6% with moxifloxacin (treatment difference, −3.9% [95% CI, −8.2%-0.5%]); noninferiority of lefamulin was demonstrated.

Secondary End Point(s)

• Response (ECR) and success (IACR) by baseline pathogen in the microbiological ITT population did not differ substantially between the treatment groups, but comparisons were limited by small numbers of patients in the subgroups by pathogen. The ECR ranged from 81.3% (L pneumophila) to 100% (S aureus, M pneumoniae) for lefamulin and from 91.3% (S pneumoniae) to 100% (S aureus, M catarrhalis, M pneumoniae, C pneumoniae) for moxifloxacin. The IACR ranged from 75% (C pneumoniae) to 95% (M pneumoniae) for lefamulin and from 83.3% (S aureus, H influenzae, C pneumoniae) to 100% (M catarrhalis, M pneumoniae) for moxifloxacin.

• The ECR response rates by PORT risk class did not significantly differ between groups (ITT population): For PORT risk classes II, III, and IV, the rates were 91.8%, 91%, and 85%, respectively, with lefamulin and 93.1%, 90.2%, and 85.7%, respectively, with moxifloxacin.

• Comments: For ECR and IACR, lefamulin noninferiority vs moxifloxacin was concluded if the lower limit of the 2-sided 95% CI for the treatment difference exceeded −10%.

• Limitations: Results are only available in a meeting abstract and poster, and in the lefamulin prescribing information. The study included a small number of patients with severe disease (PORT risk class V).

Contraindications, Warnings, and Precautions

Contraindications

Lefamulin is contraindicated in patients with known hypersensitivity to lefamulin, to the pleuromutilin class of drugs, or to any components of the formulation (tablets: colloidal silicon dioxide, croscarmellose sodium, FD&C Blue No. 2 aluminum lake, ferrosoferric oxide, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, povidone K30, shellac glaze, talc, and titanium dioxide; injection diluent: citric acid anhydrous, sodium chloride, and trisodium citrate dihydrate). ¹

Lefamulin is also contraindicated with the use of sensitive CYP3A4 substrates that prolong the QT interval (eg, pimozide) because of the potential for increased plasma concentration of these drugs leading to QT prolongation and cases of torsades de pointes. ¹

Warnings and Precautions

Lefamulin has the potential to prolong the QT interval on electrocardiogram (ECG). Lefamulin should be avoided in patients with known prolongation of the QT interval or ventricular arrhythmias, including torsades de pointes; in patients receiving class IA (eg, quinidine, procainamide) or class III (eg, amiodarone, sotalol) antiarrhythmic agents; and in 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 lefamulin cannot be avoided in patients predisposed to QT prolongation or in those receiving another drug that prolongs the QT interval, ECG monitoring is recommended during treatment. The magnitude of QT prolongation may increase with increased concentrations of lefamulin or with an increased infusion rate of the IV formulation; therefore, the recommended dose and infusion rate should not be exceeded. ¹

Clostridioides difficile–associated diarrhea (CDAD) has been reported with most antibacterial agents, including lefamulin, and may range in severity from mild diarrhea to fatal colitis. Clostridioides difficile–associated diarrhea must be considered in all patients presenting with diarrhea following antibacterial use. ¹

To reduce the risk of development of drug-resistant bacteria, lefamulin should only be used in the treatment of infection proven or strongly suspected to be caused by susceptible bacteria. ¹

Based on findings from animal studies, lefamulin may cause fetal harm when administered to pregnant women. Pregnancy status in women of reproductive potential must be verified prior to initiating lefamulin therapy. Women of reproductive potential should be advised to use effective contraception during lefamulin treatment and for 2 days after the final dose. A pregnancy pharmacovigilance program has been established (1-855-5NABRIVA); health care professionals should report lefamulin exposure if the drug is inadvertently administered during pregnancy or if a patient becomes pregnant while receiving lefamulin. ¹

There are no data regarding the presence of lefamulin in human milk, or its effects on breastfeeding infants or milk production. Animal studies showed that lefamulin was concentrated in the milk of lactating rats. Because of the potential for serious adverse reactions in a breastfeeding infant, including QT prolongation, a woman should pump and discard her milk for the duration of treatment with lefamulin and for 2 days after the final dose. ¹

Safety and efficacy of lefamulin have not been established in patients younger than 18 years. ¹ Initial pediatric studies are expected to be completed in 2024. ²³

Adverse Reactions

The most common adverse reactions reported with lefamulin include diarrhea, administration-site reactions, hepatic enzyme elevation, nausea, hypokalemia, insomnia, and headache. ¹ Tables 2 and 3 summarize the frequency of reactions with the injection and oral formulations.

Table 2.

Adverse Reactions (≥2% Incidence) in Patients Receiving Lefamulin (Lefamulin Evaluation Against Pneumonia 1 Study Safety Population). ¹

Adverse reaction	IV with or without a switch to oral dosing
	Lefamulin (n = 273), %	Moxifloxacin (n = 273), %
Administration-site reactions (infusion-site pain, infusion-site phlebitis, injection-site reaction)	7	3
Hepatic enzyme elevation (ALT increase, AST increase, liver function test increase)	3	3
Nausea	3	2
Hypokalemia	3	2
Insomnia	3	2
Headache	2	2

Note. IV = intravenous; ALT = alanine aminotransferase; AST = aspartate aminotransferase.

Table 3.

Adverse Reactions (≥2% Incidence) in Patients Receiving Lefamulin (Lefamulin Evaluation Against Pneumonia 2 Study Safety Population). ¹

Adverse reaction	Oral dosing
	Lefamulin (n = 368), %	Moxifloxacin (n = 368), %
Diarrhea	12	1
Nausea	5	2
Vomiting	3	1
Hepatic enzyme elevation (ALT increase, AST increase, liver function test increase)	2	2

Note. ALT = alanine aminotransferase; AST = aspartate aminotransferase.

Drug Interactions

Concomitant use of oral or IV lefamulin with strong CYP3A4 inducers or P-gp inducers decreases lefamulin AUC and C_max, which may reduce the efficacy of lefamulin. Concomitant use of lefamulin with strong CYP3A4 inducers or P-gp inducers should be avoided unless the benefit outweighs the risk. ¹

Concomitant use of oral lefamulin with strong CYP3A inhibitors or P-gp inhibitors increases lefamulin AUC, which may increase the risk of adverse reactions. Concomitant use of oral lefamulin with strong CYP3A4 inhibitors or P-gp inhibitors should be avoided; patients receiving oral lefamulin with moderate CYP3A inhibitors or P-gp inhibitors should be monitored for lefamulin adverse effects. ¹

Concomitant use of lefamulin tablets with sensitive CYP3A4 substrates increases AUC and C_max of the CYP3A4 substrates, which may increase the risk of toxicities associated with cardiac conduction. Concomitant use of oral lefamulin with CYP3A substrates known to prolong the QT interval is contraindicated. Close monitoring for adverse effects is required when using oral lefamulin concomitantly with alprazolam, diltiazem, verapamil, simvastatin, or vardenafil. Concomitant use of injectable lefamulin with CYP3A substrates does not affect exposure to the CYP3A substrates. ¹

The pharmacodynamic interaction potential to prolong the QT interval between lefamulin and other drugs that effect cardiac conduction is unknown. Concomitant use of injectable or oral lefamulin with drugs known to affect cardiac conduction (eg, class IA and III antiarrhythmics, antipsychotics, erythromycin, moxifloxacin, tricyclic antidepressants) should be avoided. ¹

Recommended Monitoring

Hepatic function should be assessed; ECG should be monitored in patients predisposed to or with risk factors for QT prolongation. Prior to initiating therapy, pregnancy status must be verified in women of reproductive potential. ¹

Dosing

The recommended lefamulin dosage is 150 mg every 12 hours by IV infusion over 60 minutes for 5 to 7 days, or 600 mg orally every 12 hours for 5 days. Intravenous dosing can be switched to oral lefamulin therapy (600 mg every 12 hours) to complete the treatment course. ¹ The oral dose should be administered at least 1 hour before or 2 hours after a meal. The tablets should be swallowed whole with 6 to 8 ounces of water. ¹

Prior to administration, the injectable lefamulin solution must be diluted in a 250 mL solution of 10 mM citrate-buffered sodium chloride 0.9% using the aseptic technique. The diluent IV bag should not be used in series connections, and no other additives should be added to the bag. ¹

In patients with severe hepatic impairment (Child-Pugh class C), the dosage of lefamulin injection should be reduced to 150 mg administered by IV infusion over 60 minutes every 24 hours; no adjustment to the injectable dosage is required for patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. In patients with mild hepatic impairment, no adjustment to the oral dosage is required. Oral lefamulin has not been studied in and is not recommended in patients with moderate or severe hepatic impairment. ¹ No dosage adjustments are required in patients with renal impairment. ¹

Product Availability and Storage

Lefamulin tablets and injection received FDA approval on August 19, 2019. ²³ The oval, film-coated tablets contain 671 mg of lefamulin acetate (equivalent to 600 mg of lefamulin) and are supplied in HDPE (high-density polyethylene) bottles containing 30 tablets. ¹ The injection is supplied as a clear, colorless, sterile, nonpyrogenic solution for IV administration containing 168 mg of lefamulin acetate (equivalent to 150 mg of lefamulin) in 15 mL of sodium chloride 0.9% in a single-dose vial. The vial must be diluted using the supplied infusion bags containing 250 mL of 10 mM citrate-buffered (pH 5) sodium chloride 0.9%. The vials are packaged in cartons of 6, and the citrate-buffered diluent bags are separately packaged in cartons of 6. ¹

Lefamulin injection should be stored at 2°C to 8°C (36°F-46°F). The diluent bags should be stored at 20°C to 25°C (68°F-77°F), with excursions permitted between 15°C and 30°C (59°F and 86°F). After dilution, the injectable solution may be stored for up to 24 hours at room temperature or for up to 48 hours when refrigerated at 2°C to 8°C (36°F-46°F). Lefamulin tablets should also be stored at 20°C to 25°C (68°F-77°F), with excursions permitted between 15°C and 30°C (59°F and 86°F). ¹

Drug Safety/Risk Evaluation and Mitigation Strategy

No Risk Evaluation and Mitigation Strategy (REMS) is required for lefamulin. ²³

Conclusion

Lefamulin, a pleuromutilin, is approved by the FDA for the treatment of adults with CABP caused by susceptible microorganisms. Lefamulin is available as an IV or oral formulation, and efficacy is supported by 2 phase 3 clinical studies demonstrating noninferiority to moxifloxacin in the treatment of CABP. Use should be limited to infections suspected or observed to be resistant to alternative agents. Adverse event and drug interaction data are limited.