lefamulin (Rx)

>10%

Diarrhea (12%)

1-10%

Hepatic enzyme elevation (2-3%)

Nausea (3-5%)

Hypokalemia (3%)

Insomnia (3%)

Vomiting (3%)

Headache (2%)

<2%

• Blood and lymphatic system disorders: Anemia, thrombocytopenia
• Cardiac disorders: Atrial fibrillation, palpitations
• Gastrointestinal disorders: Abdominal pain, constipation, dyspepsia, epigastric discomfort, erosive gastritis
• Infections and infestations: Clostridioides (Clostridium) difficile colitis, oropharyngeal candidiasis, vulvovaginal candidiasis
• Investigations: Alkaline phosphatase increased, creatine phosphokinase increased, electrocardiogram QT prolonged, gamma-glutamyl transferase increased
• Nervous system disorders: Somnolence
• Psychiatric disorders: Anxiety
• Renal and urinary disorders: Urinary retention

Contraindications

Hypersensitivity

Coadministration with sensitive CYP3A4 substrates that prolong QT interval

Cautions

Prescribing antibiotics in the absence of proven or strongly suspected bacterial infection increases risk of drug-resistant bacteria developing

C difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including lefamulin; if suspected or confirmed, ongoing antibacterial drug use not directed against C difficile may need to be discontinued and treatment modalities specific for C difficile initiated; evaluate patients who develop diarrhea

Based on animal studies, may cause fetal harm

QT prolongation

• Potential to prolong QT interval
• Avoid in patients with known QT prolongation, ventricular arrhythmias including torsades de pointes, or receiving other drugs known to prolong QT interval (eg, Class IA or Class III antiarrhythmics, antipsychotics, erythromycin, pimozide, moxifloxacin, TCAs)
• In patients with hepatic impairment or renal failure who require dialysis, metabolic disturbances associated with renal failure may lead to QT prolongation
• If unable to avoid use in specific populations predisposed to QT prolongation or those receiving another drug that prolongs the QT interval, ECG monitoring is recommended during treatment
• The magnitude of QT prolongation may increase with increasing lefamulin concentrations or increasing IV infusion rate; do not exceed recommended dose or infusion rate

Drug interactions overview

• Lefamulin is a CYP3A4 and P-gp substrate; it is also a moderate CYP3A4 inhibitor
• Strong or moderate CYP3A or P-gp inducers: Avoid coadministration
• Strong CYP3A or P-gp inhibitors: Avoid coadministration
• Moderate CYP3A or P-gp inhibitors: Monitor for lefamulin adverse effects
• Sensitive CYP3A4 substrates that prolong QT interval: Contraindicated
• Other sensitive CYP3A4 substrates: Monitor for adverse effects of sensitive CYP3A4 substrates if coadministered with lefamulin tablets (injection does not affect exposure of CYP3A4 substrates
• Other drugs that prolong QT interval: If unable to avoid, ECG monitoring is recommended during treatment

Pregnancy

Based on animal studies, may cause fetal harm

Verify pregnancy status in women of reproductive potential before starting treatment

Animal studies

• Animal studies indicate that IV administration 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 AUC[0-24h]), decreased fetal body weights, apparent delay in sexual maturation that suggests treatment-related developmental delay, and malformations

Contraception

• Advise females of reproductive potential to use contraception during treatment and for 2 days after final dose

Lactation

No data are available on the presence of lefamulin in human milk, the effects on the breastfed infant, or the effects on milk production

Available data in animals have shown lefamulin excreted in milk

If a drug is present in animal milk, it is likely the drug will be present in human milk

Owing to the potential for serious adverse effects, instruct lactating women to pump and discard milk for the duration of treatment and for 2 days after final dose

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Pleuromutilin antibacterial; 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

Absorption

• Oral bioavailability: ~25%
• Peak plasma time: 0.88-2 hr (PO)

Peak plasma concentration, steady-state

• IV: 3.6 mcg/mL
• PO: 2.24 mcg/mL; decreased by 22.9% with food

AUC, steady-state

• IV: 28.6 mcgh/mL
• PO: 32.7 mcgh/mL; decreased by 18.43% with food

Distribution

Protein bound: 94.8-97.1%

Vd: 86.1 L

Metabolism

Primarily metabolized by CYP3A4

Elimination

Half-life: 8 hr

Total body clearance: 11.9 L/hr

Excretion

• IV

  • Feces: 77.3% (4.2-9.1% unchanged)
  • Urine: 15.5% (9.6-14.1% unchanged)

• PO

  • Feces: 88.5% (7.8-24.8% unchanged)
  • Urine: 5.3%

IV Preparation

Further dilution required

• Dilute vial contents (ie, 150mg/15mL) in the supplied diluent bag containing 250 mL of 10 mM citrate buffered 0.9% NaCl
• Visually inspect diluent bag for particulate matter and discoloration; use only if solution is clear and container is undamaged
• Do not use diluent bag in series connections
• Do not add other additives to the diluent bag; compatibilities not established

IV Administration

Infuse IV over 1 hr

Oral Administration

Administer tablet at least 1 hr before or 2 hr after meals

Swallow tablets whole with water (6-8 oz); do not crush or divide

Missed Dose

>8 hr before next scheduled dose: Take missed dose as soon as possible

<8 hr before next scheduled dose: Do not take the missed dose; resume dosing at the next scheduled dose

Storage

Tablets: Store at room temperature of 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)

IV

• Before dilution

• Vials: Refrigerate at 2-8ºC (36-46ºF); do not freeze
• Diluent bags: Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)

• After dilution

• Room temperature: Up to 24 hr
• Refrigerated at 2-8ºC (36-46ºF): Up to 48 hr