Lefamulin

Brand names: Xenleta
Drug class: Antineoplastic Agents

Usage of 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).

Relate drugs

How to use Lefamulin

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.

Warnings

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.

    What other drugs will affect 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

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