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.

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 (QT_c) 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.

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.

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