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Lefamulin

Class: Pleuromutilins
VA Class: AM900
Chemical Name: 2-[[(1R,2R,4R)-4-amino-2-hydroxycyclohexyl]thio]-, (3aS,4R,5S,6S,8R,9R,9aR,10R)-6-ethenyldecahydro-5-hydroxy-4,6,9,10-tetramethyl-1-oxo-3a,9-propano-3aH-cyclopentacycloocten-8-yl ester
Molecular Formula: C28H45NO5S • C2H4O2
CAS Number: 1350636-82-6
Brands: Xenleta

Medically reviewed by Drugs.com on Nov 15, 2021. Written by ASHP.

Introduction

Antibacterial; pleuromutilin.

Uses for Lefamulin

Community-acquired Pneumonia

Treatment of community-acquired bacterial pneumonia (CABP) caused by susceptible Streptococcus pneumoniae, Staphylococcus aureus (methicillin-susceptible [oxacillin-susceptible] strains), Haemophilus influenzae, Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydophila pneumoniae (formerly Chlamydia pneumoniae).

Lefamulin Dosage and Administration

Administration

Administer orally or by slow IV infusion.

Oral Administration

Administer tablets orally on an empty stomach (i.e., at least 1 hour before or 2 hours after a meal). (See Food under Pharmacokinetics.)

Swallow tablets whole with 6–8 ounces of water; do not cut, chew or crush.

IV Administration

Administer by IV infusion.

Lefamulin injection concentrate must be diluted prior to IV infusion using the citrate-buffered 0.9% sodium chloride diluent provided by the manufacturer.

Do not use IV infusion bag containing diluted lefamulin solution in series connections; do not introduce additives into the diluted solution.

Dilution

Transfer entire contents of a 15-mL single-dose vial containing lefamulin injection concentrate (150 mg) into the 250-mL IV infusion bag containing citrate-buffered 0.9% sodium chloride injection provided by the manufacturer and mix thoroughly.

Do not dilute in any other diluents.

The diluted IV solution should appear clear and colorless.

Rate of Administration

Administer by IV infusion over 1 hour.

Do not exceed recommended dosage and IV infusion rate. (See Prolongation of QT Interval under Cautions.)

Dosage

Available as lefamulin acetate; dosage expressed in terms of lefamulin.

Adults

Community-acquired Pneumonia
Oral

600 mg every 12 hours for 5 days.

IV

150 mg by IV infusion every 12 hours for 5–7 days.

May switch to oral lefamulin (600 mg every 12 hours) at discretion of clinician to complete a total treatment duration (IV and oral) of 5–7 days.

Prescribing Limits

Adults

Community-acquired Pneumonia
Oral

Maximum 600 mg every 12 hours for 5 days.

IV

Maximum 150 mg by IV infusion every 12 hours for 5–7 days.

Special Populations

Hepatic Impairment

Oral

Mild hepatic impairment (Child-Pugh class A): Dosage adjustments not needed.

Moderate or severe hepatic impairment (Child-Pugh class B or C): Not recommended; pharmacokinetics not evaluated.

Monitor for adverse effects. (See Hepatic Impairment under Cautions.)

IV

Mild or moderate hepatic impairment (Child-Pugh class A or B): Dosage adjustments not needed.

Severe hepatic impairment (Child-Pugh class C): 150 mg by IV infusion every 24 hours.

Monitor for adverse effects. (See Hepatic Impairment under Cautions.)

Renal Impairment

Oral or IV

Mild, moderate, or severe renal impairment, including those receiving hemodialysis: Dosage adjustments not needed. (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations.

Cautions for Lefamulin

Contraindications

  • Known hypersensitivity to lefamulin, other pleuromutilins, or any ingredient in the formulation.

  • Concomitant use of oral lefamulin with sensitive CYP3A4 substrates (e.g., pimozide) that prolong the QT interval. (See Specific Drugs under Interactions.)

Warnings/Precautions

Prolongation of QT Interval

Prolongation of corrected QT (QTc) interval reported. Appears to occur in a plasma concentration-dependent manner; do not exceed recommended dosage and IV infusion rate.

Increased risk of QT interval prolongation and torsades de pointes if sensitive CYP3A4 substrates that prolong the QT interval are used concomitantly with oral lefamulin. Concomitant use may result in increased plasma concentrations of such drugs and may lead to QT interval prolongation and torsades de pointes; concomitant use with oral lefamulin is contraindicated.

Avoid lefamulin in patients with known QT interval prolongation or ventricular arrhythmias (including torsades de pointes). If lefamulin cannot be avoided in such patients, monitor ECGs.

Concomitant use of class IA (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol) antiarrhythmic agents or other drugs that prolong the QT interval (e.g., erythromycin, pimozide, moxifloxacin, antipsychotic agents, tricyclic antidepressants) may increase the risk of QT interval prolongation; avoid concomitant use with these agents. If concomitant use cannot be avoided, monitor ECGs.

Risk of prolonged QT interval may be increased in patients with mild, moderate, or severe hepatic impairment and in patients with renal failure requiring dialysis since metabolic disturbances associated with hepatic insufficiency and renal failure may lead to QT interval prolongation. If lefamulin cannot be avoided in such patients, monitor ECGs.

Fetal/Neonatal Morbidity and Mortality

Based on animal findings, may cause fetal harm if used in pregnant women. Embryofetal toxicity, lethality, and teratogenicity demonstrated in animals.

Perform pregnancy test prior to initiating lefamulin in women of childbearing potential; pregnancy should be avoided during therapy with the drug. (See Females of Reproductive Potential under Cautions.)

Superinfection/Clostridioides difficile-associated Diarrhea and Colitis (CDAD)

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridioides difficile (formerly Clostridium difficile).

C. difficile infection (CDI) and C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) reported with nearly all anti-infectives, including lefamulin, and may range in severity from mild diarrhea to fatal colitis. C. difficile produces toxins A and B which contribute to the development of CDAD; hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.

Consider CDAD if diarrhea develops during or after therapy and manage accordingly. Obtain careful medical history since CDAD may occur as late as 2 months or longer after anti-infective therapy is discontinued.

If CDAD is suspected or confirmed, discontinue anti-infectives not directed against C. difficile whenever possible. Initiate appropriate anti-infective therapy directed against C. difficile (e.g., fidaxomicin, vancomycin, metronidazole), supportive therapy (e.g., fluid and electrolyte management, protein supplementation), and surgical evaluation as clinically indicated.

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of lefamulin and other antibacterials, use only for treatment of infections proven or strongly suspected to be caused by susceptible bacteria.

When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing. In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.

Information on test methods and quality control standards for in vitro susceptibility testing of antibacterial agents and specific interpretive criteria for such testing recognized by FDA is available at [Web].

Specific Populations

Pregnancy

Data not available on use of lefamulin in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Based on animal studies, may cause fetal harm if used in pregnant women. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

If lefamulin inadvertently administered during pregnancy or if pregnancy occurs while receiving the drug, report the exposure to lefamulin pregnancy pharmacovigilance program at 855-562-2748.

Lactation

Not known whether lefamulin distributes into human milk, affects milk production, or affects nursing infants. Distributed into milk in rats.

Because of potential for serious adverse reactions to lefamulin in nursing infants (e.g., QT interval prolongation), women should not breast-feed while receiving lefamulin and for 2 days after the last dose.

Females of Reproductive Potential

Perform pregnancy testing prior to initiating lefamulin in females of reproductive potential.

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

Pediatric Use

Safety and efficacy not established in patients <18 years of age.

Geriatric Use

In clinical studies evaluating lefamulin, 41.5% of patients were ≥65 years of age. No overall differences in safety or efficacy observed between these geriatric patients and younger adults.

Hepatic Impairment

Metabolic disturbances associated with hepatic impairment may lead to QT interval prolongation. Monitor ECGs during oral or IV lefamulin therapy in patients with hepatic impairment. (See Prolongation of QT Interval under Cautions)

IV: Half-life is increased, protein binding is reduced, and AUC of unbound lefamulin is increased threefold following IV administration in patients with severe hepatic impairment (Child-Pugh class C). Adjust dosage of IV lefamulin in patients with severe hepatic impairment. (See Hepatic Impairment under Dosage and Administration.)

Oral: Not recommended in patients with moderate or severe hepatic impairment (Child-Pugh class B or C); pharmacokinetics of oral lefamulin not evaluated in patients with hepatic impairment;

Renal Impairment

Metabolic disturbances associated with renal failure requiring dialysis may lead to QT interval prolongation. Monitor ECGs during oral or IV lefamulin therapy in such patients. (See Prolongation of QT Interval under Cautions.)

Pharmacokinetics of lefamulin not affected by renal impairment.

Common Adverse Effects

Oral: Diarrhea, nausea, vomiting, hepatic enzyme elevation.

IV: Administration site reactions (infusion site pain, phlebitis), hepatic enzyme elevation, nausea, hypokalemia, insomnia, headache.

Interactions for Lefamulin

Metabolized primarily by CYP3A4.

In vitro, lefamulin inhibits CYP2C8, breast cancer resistance protein (BCRP), and multidrug and toxin extrusion (MATE) transporter 1.

Drugs Affecting by Hepatic Microsomal Enzymes

Moderate and potent inhibitors of CYP3A: Potential pharmacokinetic interaction (increased lefamulin exposure) and possible increased risk of toxicity if used with oral lefamulin.

Moderate and potent inducers of CYP3A: Potential pharmacokinetic interaction (decreased lefamulin exposure) and possible reduced therapeutic efficacy if used with oral or IV lefamulin.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A: Potential pharmacokinetic interaction with oral lefamulin (increased exposure of CYP3A substrate and possible increased risk of adverse effects of CYP3A substrate). No clinically important interaction with IV lefamulin.

Drugs Affecting or Affected by Membrane Transporters

Inhibitors of P-glycoprotein (P-gp): Potential pharmacokinetic interaction (increased lefamulin exposure) and possible increased toxicity if used with oral lefamulin.

Inducers of P-glycoprotein (P-gp): Potential pharmacokinetic interaction (decreased lefamulin exposure) and possible reduced therapeutic efficacy.

Drugs that Prolong the QT Interval

Potential pharmacologic interaction (increased risk of QT interval prolongation). Avoid concomitant use with other drugs known to prolong the QT interval.

Specific Drugs

Drug

Interaction

Comments

Alprazolam

Alprazolam (sensitive CYP3A substrate): Possible increased alprazolam exposure and increased risk of alprazolam-associated adverse effects if used with oral lefamulin; no effect on alprazolam exposure expected if used with IV lefamulin

If sensitive CYP3A substrate used concomitantly with oral lefamulin, monitor closely for toxicities related to the CYP3A substrate

Antiarrhythmics, class IA (e.g., quinidine, procainamide) or III (e.g., amiodarone, sotalol)

Possible increased risk of prolonged QT interval

Avoid concomitant use with drugs known to prolong QT interval; if concomitant use cannot be avoided, monitor ECGs

Antibacterials

Doxycycline: Synergistic antibacterial effects against S. aureus in vitro

Amikacin, azithromycin, aztreonam, ceftriaxone, levofloxacin, linezolid, meropenem, penicillin, tigecycline, trimethoprim/sulfamethoxazole, vancomycin: No in vitro evidence of antagonism with lefamulin

Antidepressants known to prolong QT interval (e.g., tricyclics)

Possible increased risk of prolonged QT interval

Avoid concomitant use with drugs known to prolong QT interval; if concomitant use cannot be avoided, monitor ECGs

Antipsychotics known to prolong QT interval (e.g., pimozide)

Pimozide (sensitive CYP3A substrate that prolongs the QT interval): Possible increased pimozide exposure and increased risk of pimozide-associated adverse effects with oral lefamulin

Possible increased risk of prolonged QT interval

Pimozide: Concomitant use with oral lefamulin contraindicated

Other antipsychotics known to prolong QT interval: Avoid concomitant use; if concomitant use cannot be avoided, monitor ECGs

Digoxin

No effect on digoxin pharmacokinetics if used with oral lefamulin

Diltiazem

Diltiazem (sensitive CYP3A substrate): Possible increased diltiazem exposure and increased risk of diltiazem-associated adverse effects if used with oral lefamulin; no effect on diltiazem exposure expected if used with IV lefamulin

If sensitive CYP3A substrate used concomitantly with oral lefamulin, monitor closely for toxicities related to the CYP3A substrate

Erythromycin

Possible increased risk of prolonged QT interval

Avoid concomitant use with drugs known to prolong QT interval; if concomitant use cannot be avoided, monitor ECGs

Ketoconazole

Ketoconazole (potent CYP3A inhibitor): Increased lefamulin peak plasma concentration and AUC; possible increased risk of lefamulin toxicity

Potent CYP3A inhibitors: Avoid concomitant use

Midazolam

Midazolam (sensitive CYP3A substrate): Increased midazolam peak plasma concentration and AUC if used with oral lefamulin; no clinically important effect on midazolam exposure if used with IV lefamulin

If used concomitantly with oral lefamulin, monitor closely for CYP3A substrate-related toxicities

Moxifloxacin

Possible increased risk of prolonged QT interval

Avoid concomitant use with other drugs known to prolong QT interval; if concomitant use cannot be avoided, monitor ECGs

Rifampin

Rifampin (potent CYP3A inducer): Decreased lefamulin peak plasma concentration and AUC and possible decreased lefamulin efficacy if used with oral or IV lefamulin

Avoid concomitant use unless benefits outweigh risks

Simvastatin

Simvastatin (sensitive CYP3A substrate): Possible increased simvastatin exposure and increased risk of simvastatin-associated adverse effects if used with oral lefamulin; no effect on simvastatin exposure expected if used with IV lefamulin

If sensitive CYP3A substrate used concomitantly with oral lefamulin, monitor closely for toxicities related to the CYP3A substrate

Vardenafil

Vardenafil (sensitive CYP3A substrate): Possible increased vardenafil exposure and increased risk of vardenafil-associated adverse effects if used with oral lefamulin; no effect on vardenafil exposure expected if used with IV lefamulin

If sensitive CYP3A substrate used concomitantly with oral lefamulin, monitor closely for toxicities related to the CYP3A substrate

Verapamil

Verapamil (sensitive CYP3A substrate): Possible increased verapamil exposure and increased risk of verapamil-associated adverse effects if used with oral lefamulin; no effect on verapamil exposure expected if used with IV lefamulin

If sensitive CYP3A substrate used concomitantly with oral lefamulin, monitor closely for toxicities related to the CYP3A substrate

Lefamulin Pharmacokinetics

Absorption

Bioavailability

Oral: Absolute bioavailability approximately 25% following administration of tablets. Peak plasma concentrations attained 0.88–2 hours after a dose. Following single oral doses ranging from 500–750 mg, AUC increases in more than a dose-proportional manner.

IV: Peak plasma concentrations attained at the end of a 60-minute IV infusion. Following single IV doses ranging from 25–400 mg, AUC increases in an approximately dose-proportional manner; peak plasma concentration increases in a less than dose-proportional manner.

In healthy adults, systemic exposures are similar following a single 600-mg oral dose (given in fasted state) or a single 150-mg IV dose.

In patients with CABP, mean lefamulin AUC and peak plasma concentration are 73 and 30% higher, respectively, compared with that reported in healthy individuals.

Food

Single 600-mg oral dose with a high-fat, high-calorie meal decreased peak plasma concentration and AUC by 23 and 18%, respectively, compared with administration in fasted state.

Special Populations

Severe hepatic impairment (Child-Pugh class C): AUC of unbound drug increased threefold.

Distribution

Extent

Mean steady-state volume of distribution approximately 86 L following IV administration, which suggests extensive tissue distribution.

Plasma Protein Binding

95–97%.

Special Populations

Hepatic Impairment: Protein binding decreases depending on degree of hepatic impairment.

Elimination

Metabolism

Primarily metabolized by CYP3A4.

Elimination Route

Oral: Approximately 89% of a dose eliminated in feces (8–25% as unchanged drug) and 5% in urine (as unchanged drug and metabolites).

IV: Approximately 77% of a dose eliminated in feces (4–9% as unchanged drug) and 16 % in urine (10–14% as unchanged drug).

Lefamulin and primary metabolite not removed by dialysis.

Half-life

Patients with CABP: Approximately 8 hours (range: 3–20 hours).

Special Populations

Severe hepatic impairment (Child-Pugh class C): Half-life prolonged compared to that in individuals with normal hepatic function (17.5 versus 11.5 hours).

Renal impairment (including those on hemodialysis): No clinically important difference in pharmacokinetics.

No clinically important differences in pharmacokinetics based on age, sex, race, or body weight.

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).

Parenteral

Injection Concentrate

Single-dose vials of solution concentrate: 2–8°C. Do not freeze.

Infusion bags of citrate-buffered 0.9% sodium chloride diluent: 2–25°C in barrier overwrap.

Diluted solution for IV infusion: Room temperature for up to 24 hours or 2–8° for up to 48 hours after dilution.

Actions and Spectrum

  • Semisynthetic pleuromutilin antibiotic.

  • Selectively inhibits protein synthesis in susceptible bacteria through interactions (i.e., hydrogen bonds, hydrophobic interactions, Van der Waals forces) with the A- and P-sites of the peptidyl transferase center (PTC) in the 50S subunit of the bacterial ribosome, thereby preventing correct positioning of tRNA, inhibiting peptidyl transfer, blocking P-site interactions, and preventing normal formation of active 50S ribosomal subunits.

  • Active in vitro and in clinical infections against some gram-positive bacteria, including Streptococcus pneumoniae and Staphylococcus aureus (methicillin-susceptible strains), and some gram-negative bacteria, including Haemophilus influenzae and Legionella pneumophila. Also active in vitro and in clinical infections against Mycoplasma pneumoniae (including macrolide-resistant strains) and Chlamydophila pneumoniae (formerly Chlamydia pneumoniae).

  • Although active in vitro against methicillin-resistant S. aureus (MRSA; also known as oxacillin-resistant S. aureus or ORSA), S. pyogenes (group A β-hemolytic streptococci; GAS), S. agalactiae (group B streptococci; GBS), S. anginosus, S. mitis, S. salivarius, H. parainfluenzae, and Moraxella catarrhalis, safety and efficacy for treatment of clinical infections caused by these bacteria not established.

  • Not active against Enterococcus faecalis, Enterobacteriaceae, Acinetobacter baumannii, or Pseudomonas aeruginosa.

  • Low frequency of educed susceptibility or resistance to lefamulin due to spontaneous mutations.

  • Resistance mechanisms that may affect susceptibility to lefamulin include modification or mutations of certain ribosomal target proteins, including Cfr methyl transferase, which may mediate cross-resistance to other anti-infectives that have overlapping interaction sites (e.g., oxazolidinones, lincosamides, phenicols, streptogramins). However, probability of cross-resistance between lefamulin and other anti-infectives appears to be low.

Advice to Patients

  • Advise patients that antibacterials (including lefamulin) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).

  • Advise patients that the tablets should be taken 1 hour before or 2 hours after meals and should be swallowed whole with 6–8 ounces of water.

  • Importance of completing full course of therapy, even if feeling better after a few days. Advise patients that skipping doses or not completing the full course of therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with lefamulin or other antibacterials in the future.

  • If a dose of lefamulin is missed and remembered within 4 hours after the scheduled time, the dose should be taken as soon as possible and the next dose taken at the regularly scheduled time. If a dose is missed and remembered more than 4 hours after the scheduled time, the dose should be skipped and the next dose taken at the regularly scheduled time.

  • Advise patients that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment. Inquire about any previous hypersensitivity reactions to lefamulin or other pleuromutilin antibiotics.

  • Advise patients that nausea and vomiting are common adverse effects of lefamulin. Also advise patients that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued. Importance of contacting a clinician if watery and bloody stools (with or without stomach cramps and fever) occur during or as late as 2 months or longer after the last dose.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

  • Importance of women informing clinicians if they are or plan to become pregnant. Inform women of reproductive potential about risk to a fetus. Advise women of reproductive potential to avoid pregnancy during lefamulin therapy and the importance of using effective contraception while receiving lefamulin and for 2 days after the last dose. Inform patients that there is a pregnancy registry to monitor fetal outcomes of pregnant women exposed to lefamulin. (See Pregnancy under Cautions.)

  • Importance of women informing clinician if they plan to breast-feed. Importance of advising women to avoid breast-feeding while receiving lefamulin and for 2 days after the last dose.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

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

Oral

Tablets, film-coated

600 mg (of lefamulin)

Xenleta

Nabriva

Parenteral

For injection concentrate, for IV infusion

10 mg (of lefamulin) per mL (150 mg)

Xenleta (with infusion bag of citrate-buffered 0.9% sodium chloride diluent)

Nabriva

AHFS DI Essentials™. © Copyright 2022, Selected Revisions November 15, 2021. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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