Drug information of lefamulin

lefamulin

Drug group:

It is a semi-synthetic antibacterial agent and is indicated for treatment of community-acquired bacterial pneumonia (CABP) in adults caused by susceptible microorganisms

:Susceptible bacteria
Streptococcus pneumoniae -
Staphylococcus aureus (methicillin-susceptible isolates) -
Haemophilus influenzae -
Legionella pneumophila -
Mycoplasma pneumoniae -
Chlamydophila pneumoniae -

:Dosage forms and strengths
tablet: 600 mg
intravenous solution: 150mg/15ml 0.9% NaCl (further dilution required)

Mechanism of effect

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

Pharmacodynamic

Lefamulin demonstrates strong antibacterial activity against several microbes that are found to be common in both acute bacterial skin and skin structure infections as well as community-acquired bacterial pneumonia. It shows antibacterial activity against gram-positive and atypical microbes (for example, Streptococcus pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae, Haemophilus influenzae, and Chlamydophila pneumoniae). Lefamulin also exerts activity against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus faecium. It does not treat Pseudomonas aeruginosa infections. During in vitro studies, drug has also has demonstrated activity against Neisseria gonorrhoeae and Mycoplasma genitalium

:A note on QT prolongation and Clostridium difficile
According to the FDA label, lefamulin may have cardiac QT interval prolonging effects and advises against the administration of this drug in patients with diagnosed QT prolongation or ventricular arrhythmias. The administration of lefamulin should also be avoided in patients being administered antiarrhythmic agents and other drugs that prolong the QT interval. As with other antibiotics, the risk of Clostridium difficile associated diarrhea is increased with lefamulin use. Any case of diarrhea should be evaluated for C. difficile

Pharmacokinetics

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

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%

Dosage

:Community AcquiredBactrial Pneumonia
150mg IV infusion q12hr (over 60 minutes) x 5-7 days OR 600mg PO q12 hr x 5 days
.May switch from IV to oral to complete treatment course
 .For patients with severe hepatic impairment, dosage adjustment is required

Alerts

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

:About QT Prolongation
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

Points of recommendation

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
more than 8hr before next scheduled dose: Take missed dose as soon as possible
less than 8hr before next scheduled dose: Do not take the missed dose; resume dosing at the next scheduled dose

:Significant Adverse effects
Diarrhea
QT Prolongation
Hepatic enzyme elevation
Nausea
Hypokalemia
Insomnia
Vomiting
Headache

:Obsolete Adverse Reactions
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

:Interactions
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

:Contraindications
Hypersensitivity
Coadministration with sensitive CYP3A4 substrates that prolong QT interval

Pregnancy level

Based on animal studies, may cause fetal harm
Verify pregnancy status in women of reproductive potential before starting treatment
Advise females of reproductive potential to use contraception during treatment and for 2 days after final dose

Breast feeding warning

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

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