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Lefamulin Acetate

Class: Pleuromutilins
Chemical Name: [(1S,2R,3S,4S,6R,7R,8R)-4-ethenyl-3-hydroxy-2,4,7,14-tetramethyl-9-oxo-6-tricyclo[5.4.3.01,8]tetradecanyl] 2-[(1R,2R,4R)-4-amino-2-hydroxycyclohexyl]sulfanylacetate
Molecular Formula: C28H45NO5S
Brands: Xenleta

Medically reviewed by Drugs.com. Last updated on Sep 16, 2019.

Introduction

Lefamulin acetate is a pleuromutilin antibiotic.

Uses for Lefamulin Acetate

Lefamulin acetate has the following uses:

Lefamulin acetate is a pleuromutilin antibacterial indicated in adults for the treatment of community-acquired bacterial pneumonia (CABP) caused by susceptible microorganisms.1

To reduce the development of drug resistant bacteria and maintain the effectiveness of lefamulin acetate and other antibacterial drugs, lefamulin acetate should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.1

Lefamulin Acetate Dosage and Administration

General

Lefamulin acetate is available in the following dosage form(s) and strength(s):

Injection1

  • Single-dose clear glass vial containing 150 mg of lefamulin in 15 mL of 0.9% sodium chloride for further dilution prior to intravenous infusion.1

Tablets1

  • 600 mg of lefamulin.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration
  • For treatment of adults with CABP, the recommended dosage of lefamulin acetate is as follows:1

With the option to switch to lefamulin acetate tablets (600 mg of lefamulin orally every 12 hours) to complete the treatment course.

Dosage

Treatment Duration

150 mg of lefamulin every 12 hours by intravenous infusion over 60 minutes

5 to 7 days

600 mg of lefamulin orally every 12 hours

5 days

  • Patients with Hepatic Impairment: Reduce the dosage of lefamulin acetate injection to 150 mg of lefamulin by intravenous infusion over 60 minutes every 24 hours in patients with severe hepatic impairment (Child-Pugh Class C). Lefamulin acetate tablets have not been studied in and are not recommended for patients with moderate or severe hepatic impairment (Child-Pugh Class B or C).1

  • Administration Instruction for Lefamulin Acetate Tablets: Take at least 1 hour before a meal or 2 hours after a meal. Swallow lefamulin acetate tablets whole with water (6 to 8 ounces).1

  • Administration Instruction for Lefamulin Acetate Injection: Infuse over 60 minutes.1

  • See full prescribing information for additional information on the administration and preparation of lefamulin acetate tablets and injection.1

Cautions for Lefamulin Acetate

Contraindications

  • Lefamulin acetate is contraindicated in patients with known hypersensitivity to lefamulin, pleuromutilin class drugs, or any of the components of lefamulin acetate.1

  • Concomitant use of lefamulin acetate tablets with CYP3A substrates that prolong the QT interval is contraindicated.1

Warnings/Precautions

QT Prolongation

Lefamulin acetate has the potential to prolong the QT interval of the electrocardiogram (ECG) in some patients. Avoid lefamulin acetate use in the following patients:1

  • Patients with known prolongation of the QT interval1

  • Patients with ventricular arrhythmias including torsades de pointes1

  • Patients receiving Class IA (for example, quinidine, procainamide) or Class III (for example, amiodarone, sotalol) antiarrhythmic agents1

  • Patients receiving other drugs that prolong the QT interval, such as antipsychotics, erythromycin, pimozide, moxifloxacin, and tricyclic antidepressants1

In patients with renal failure who require dialysis, metabolic disturbances associated with renal failure may lead to QT prolongation.1

In patients with mild, moderate, or severe hepatic impairment, metabolic disturbances associated with hepatic impairment may lead to QT prolongation.1

If use with lefamulin acetate 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.1

The magnitude of QT prolongation may increase with increasing concentrations of lefamulin acetate or increasing the rate of infusion of the intravenous formulation. Therefore, the recommended dose and infusion rate should not be exceeded.1

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.1

Verify pregnancy status in females of reproductive potential prior to initiating lefamulin acetate. Advise females of reproductive potential to use effective contraception during treatment with lefamulin acetate and for 2 days after the final dose. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.1

Clostridium difficile-associated Diarrhea

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including lefamulin acetate, 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.1

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.1

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.1

Development of Drug-resistant Bacteria

Prescribing lefamulin acetate 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.1

Specific Populations

Pregnancy

Risk Summary: Based on findings from animal studies, lefamulin may cause fetal harm when administered to pregnant women. There are no available data on the use of lefamulin acetate in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.1

Animal studies indicate that intravenous administration of lefamulin during organogenesis resulted in an increased incidence of prenatal mortality at mean maternal exposures 0.9 times the mean exposure in clinical patients (based on AUC0-24h), decreased fetal body weights, apparent delay in sexual maturation that suggest treatment-related developmental delay, and malformations in rats at maternal exposures greater than 0.4 times the mean exposure in CABP patients for which the litter incidence was nonexistent in concurrent controls and rare (0 to approximately 0.3%) in historical controls. Decreased ossification was seen in fetuses at all doses in a dose-related manner, suggestive of developmental delay.1

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.1

There is a pregnancy pharmacovigilance program for lefamulin acetate. If lefamulin acetate is inadvertently administered during pregnancy or if a patient becomes pregnant while receiving lefamulin acetate, healthcare providers should report lefamulin acetate exposure by calling 1-855-5NABRIVA to enroll.1

Animal Data: In a prenatal and postnatal development study in rats treated from the beginning of organogenesis through lactation (Gestation Day [GD] 6 through lactation day 21), the percent of live births was reduced (87.4% compared with the concurrent control of 98.7%) in the high dose group of 100 mg/kg/day (0.9 times the mean exposure in CABP patients treated IV). Equivocal findings in that study were indicative of early post-natal mortality and apparent developmental delay that may be related to pre-natal effects.1

In the rat embryo-fetal development study of IV lefamulin during organogenesis (GD 6-17), findings included late resorptions in the high-dose group and malformations (cleft palate/jaw/vertebral malformations at the mid and high doses and enlarged ventricular heart chamber with a thin ventricular wall at the high dose) for which the litter incidence was nonexistent in concurrent controls and rare in historical controls (0 to approximately 0.3%). Decreased or no ossification in a number of skeletal elements in all treated groups may indicate treatment-related developmental delay at all doses. The mean exposure at the lowest dose was approximately 0.4 times the mean exposure in CABP patients treated IV. The main human metabolite, 2R-hydroxy lefamulin, was evaluated in an embryo-fetal development study in rats after IV administration and was also associated with the same cardiac malformation seen in the above study, enlarged ventricular heart chamber with or without a thin ventricular wall (which could be associated with undetected valve or great vessel anomalies).1

In the rabbit embryo-fetal development study of IV lefamulin during organogenesis (GD 6-18), low numbers of live fetuses in utero in treated groups limited evaluation of the study. Additional findings at the high dose included decreased fetal weight and decreased or no ossification of skeletal elements, which may be indicative of developmental delay. A NOAEL was not determined. The lowest dose (not fully evaluated due to fetal mortality) would correspond to a mean exposure approximately 0.1 times the mean exposure in CABP patients.1

Results of animal studies indicate that lefamulin crosses the placenta and is found in fetal tissues. Following a single intravenous administration of 30 mg/kg radio-labelled lefamulin to pregnant female rats on Day 17 of gestation, radioactivity was visible in fetal tissue, with greatest concentrations measured in the placenta and fetal liver (34.3 and 8.26 mcg equivalents/g, respectively) compared to 96.6 mcg equivalents/g in the maternal liver. Radioactivity in fetal tissues generally declined rapidly, and radioactivity associated with the fetus itself was below the limit of quantification by 12 hours post-dose. Radioactivity in the placenta declined rapidly and was below the limit of quantification by 24 hours after dosing. Concentrations of radioactivity in the amniotic sac remained measurable at the final sampling time (72 hours), peaking at 6 hours post-dose. The amniotic fluid did not contain radioactivity at any time after dose administration.1

Lactation

Risk Summary: There are no data on the presence of lefamulin acetate in human milk, its effects on the breastfed infant, or its effects on milk production. Animal studies indicate that lefamulin was concentrated in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the potential for serious adverse reactions, including QT prolongation, a woman should pump and discard human milk for the duration of treatment with lefamulin acetate and for 2 days after the final dose.1

Data: Administration of a single intravenous dose of 30 mg/kg radio-labelled lefamulin to lactating rats resulted in maximal mean concentrations of radioactivity in plasma and milk at 0.25-hour post-dose (3.29 and 10.7 mcg equivalents/g, respectively) that were markedly reduced at 24 hours post-dose (0.00663 and 0.0700 mcg equivalents/g, respectively). Milk/plasma ratios increased from 3.27 at 0.25-hour post-dose to 8.33 at 6 hours post-dose. These data indicate that pups would be exposed to lefamulin and its metabolites in maternal milk.1

Females and Males of Reproductive Potential

Verify pregnancy status in females of reproductive potential.1

Advise females of reproductive potential to use effective contraception during treatment with lefamulin acetate and for 2 days after the final dose. Lefamulin acetate may cause fetal harm when administered to a pregnant woman.1

Pediatric Use

The safety and effectiveness of lefamulin acetate in patients less than 18 years of age has not yet been established.1

Geriatric Use

Of the 646 patients randomized to lefamulin acetate in Trials 1 and 2, 268 (41.5%) were ≥65 years of age. Early clinical response (ECR) rates in the subgroup of patients ≥65 were similar to ECR rates in subjects <65 years of age and comparable across treatment groups (lefamulin acetate versus moxifloxacin).1

The adverse reaction profiles in patients ≥65 years and in patients <65 years of age were similar. The percentage of patients in the lefamulin acetate group who had at least one adverse reaction was 30% in patients ≥65 years and 38% in patients <65 years.1

Hepatic Impairment

Dosage of lefamulin acetate injection should be reduced by extending the dosing interval for patients with severe hepatic impairment (Child-Pugh Class C). No dosage adjustment of lefamulin acetate Injection is needed for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.1

Lefamulin acetate tablets have not been studied in patients with hepatic impairment. It is not recommended to use lefamulin acetate Tablets for patients with moderate or severe hepatic impairment.1

Renal Impairment

No dosage adjustment of lefamulin acetate is warranted in patients with renal impairment, including those on hemodialysis.1

Common Adverse Effects

Most common adverse reactions (incidence ≥2%) are:1

  • Lefamulin acetate Injection: Administration site reactions, hepatic enzyme elevation, nausea, hypokalemia, insomnia, headache.1

  • Lefamulin acetate Tablets: Diarrhea, nausea, vomiting, hepatic enzyme elevation.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Lefamulin Acetate Injection

-

Strong or moderate CYP3A inducers or P-gp inducers

Avoid lefamulin acetate unless the benefit outweighs the risk. Monitor for reduced efficacy.

Lefamulin Acetate Tablets

-

Strong or moderate CYP3A inducers or P-gp inducers

Avoid lefamulin acetate unless the benefit outweighs the risk. Monitor for reduced efficacy.

Strong CYP3A inhibitors or P-gp inhibitors

Avoid lefamulin acetate.

Moderate CYP3A inhibitors or P-gp inhibitors

Monitor for adverse reactions.

CYP3A substrates that prolong the QT interval

Concomitant use is contraindicated.

Midazolam and other sensitive CYP3A substrates

Monitor for adverse reactions.

Actions and Spectrum

Mechanism of Action

Lefamulin acetate is a pleuromutilin antibacterial drug.1

Lefamulin acetate 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.1

Lefamulin acetate is bactericidal in vitro against Streptococcus pneumoniae, Haemophilus influenzae and Mycoplasma pneumoniae (including macrolide-resistant strains), and bacteriostatic against Staphylococcus aureus and S. pyogenes at clinically relevant concentrations.1

Lefamulin acetate is not active against Enterobacteriaceae or Pseudomonas aeruginosa.1

Spectrum

Lefamulin acetate has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections: 1

    Gram-positive Bacteria
  • Streptococcus pneumoniae1

  • Staphylococcus aureus (methicillin-susceptible isolates)1

    Gram-negative Bacteria
  • Haemophilus influenzae1

    Other Bacteria
  • Mycoplasma pneumoniae1

  • Chlamydophila pneumoniae1

  • Legionella pneumophila1

At least 90% of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoints for lefamulin acetate against isolates of similar genus or organism group. However, the safety and efficacy of lefamulin acetate in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.1

    Gram-positive Bacteria
  • Staphylococcus aureus (methicillin-resistant [MRSA] isolates)1

  • Streptococcus agalactiae1

  • Streptococcus anginosus1

  • Streptococcus mitis1

  • Streptococcus pyogenes1

  • Streptococcus salivarius1

    Gram-negative Bacteria
  • Haemophilus parainfluenzae1

  • Moraxella catarrhalis1

In vitro studies demonstrated no antagonism between lefamulin acetate and other antibacterial drugs (e.g., amikacin, azithromycin, aztreonam, ceftriaxone, levofloxacin, linezolid, meropenem, penicillin, tigecycline, trimethoprim/sulfamethoxazole, and vancomycin).1

Lefamulin acetate has demonstrated synergy in vitro with doxycycline against S. aureus.1

Resistance

The resistance frequency to lefamulin acetate due to spontaneous mutations in vitro at 2-8 times the MIC was 2 x 10-9 to <2 x 10-11 for S. aureus, <1 x 10-9 to <3 x 10-10 for S. pneumoniae, and <4 x 10-9 to <2 x 10-10 for S. pyogenes. Resistance development at sub-MIC concentrations required greater than 1 mutational step with no resistant clones detected at ≥4-times MIC.1

Resistance mechanisms that affect lefamulin acetate include specific protection or modification of the ribosomal target by ABC-F proteins such as vga (A, B, E), lsa(E), sal(A), Cfr methyl transferase, or by mutations of ribosomal proteins L3 and L4. Cfr methyl transferase has the potential to mediate cross-resistance between lefamulin and phenicols, lincosamides, oxazolidinones, and streptogramin A antibacterials.1

Some isolates resistant to β-lactams, glycopeptides, macrolides, mupirocin, quinolones, tetracyclines, and trimethoprim-sulfamethoxazole may be susceptible to lefamulin acetate.1

Advice to Patients

Patient Counseling Information

Advise patients that diarrhea is a common problem caused by antibacterial drugs, including lefamulin acetate, which usually ends when the antibacterial drug is discontinued. Sometimes after starting treatment with an antibacterial drug, patients can develop watery stools (with or without stomach cramps and fever) which may be a sign of a more serious intestinal infection, even as late as 2 or more months after having taken the last dose of the antibacterial drug. If this occurs, instruct patients to contact their healthcare provider as soon as possible.1

Advise patients that nausea and vomiting are common adverse reactions to lefamulin acetate.1

Advise patients of the potential interaction other medications can have with lefamulin acetate or the effect lefamulin acetate may have on other medications, as these interactions may result in decreased effectiveness or increased toxicities of either lefamulin acetate or the other medications. Patients should alert their physician if they are currently taking any medication(s) (including herbal or nutritional supplements) or are prescribed new medication(s) during treatment with lefamulin acetate.1

Advise patients that allergic reactions, including serious allergic reactions, could occur with lefamulin acetate and that serious allergic reactions require immediate treatment. Ask the patient about any previous hypersensitivity reactions to lefamulin acetate, or other pleuromutilin class antibacterial drugs.1

Advise patients that lefamulin acetate should be taken at least 1 hour before a meal or 2 hours after a meal and should be swallowed whole with water (6 to 8 ounces). Lefamulin acetate should not be crushed or divided.1

Advise pregnant women and females of reproductive potential of the potential risk to a fetus, and to inform their healthcare provider of a known or suspected pregnancy. Advise patients to avoid becoming pregnant while receiving this drug.1

Advise females of reproductive potential to use effective contraception during treatment with lefamulin acetate and for 2 days after the final dose.1

Inform patients that Nabriva Therapeutics has a surveillance program for pregnant women who have inadvertently taken lefamulin acetate during pregnancy. Advise patients to call 1-855-5NABRIVA to enroll.1

Advise lactating women to pump and discard human milk for the duration of treatment with lefamulin acetate and for 2 days after the final dose.1

Patients should be counseled that antibacterial drugs including lefamulin acetate should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When lefamulin acetate is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of treatment, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by lefamulin acetate or other antibacterial drugs in the future.1

Additional Information

AHFSfirstRelease. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Lefamulin Acetate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, Solution

150 mg (of lefamulin) per 15 mL

Xenleta

Nabriva Therapeutics US Inc.

Oral

Tablet, Coated

600 mg (of lefamulin)

Xenleta

Nabriva Therapeutics US Inc.

AHFS Drug Information. © Copyright 2020, Selected Revisions September 16, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Nabriva Therapeutics US, Inc. Xenleta (lefamulin acetate) INTRAVENOUS prescribing information. 2019 Aug. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=101db63d-2fe2-48df-8506-1382d6dcd4a3