Lefamulin (Xenleta) - Class, Uses, Dose, Side effects, MOA

Lefamulin (Xenleta) is the first drug of the novel class of antibiotics called pleuromutilin. It has recently been approved by the FDA for the treatment of community-acquired bacterial pneumonia in adults.

Lefamulin (Xenleta) Uses:

Community-acquired pneumonia:
- It is indicated for the treatment of community-acquired bacterial pneumonia in adults caused by the following susceptible microorganisms:
  - Streptococcus pneumoniae,
  - Staphylococcus aureus (methicillin-susceptible isolates),
  - Haemophilus influenzae,
  - Legionella pneumophila,
  - Mycoplasma pneumoniae, and
  - Chlamydophila pneumoniae.

Lefamulin (Xenleta) Dose in Adults:

Lefamulin (Xenleta) Dose in the treatment of community-acquired Pneumonia:

- IV dose: 150 mg twiced daily.
- Oral: 600 mg twice daily.
Duration of therapy:
- The total duration of treatment is variablea nd depends on the severity oft hed isease and the response to the treatment.
- The total duration of the treatment including step-down therapy is a minimum of five days.
- Before discontinuing the treatment, the patient should be afebrile and clinically stable for at least 48 hours.
Missed dose:
- Avoid taking the missed dose if less than 8 hours are left until the next scheduled dose.

Use in children:

Not indicated.

Lefamulin (Xenleta) Pregnancy Risk Category:

In animal reproduction studies, fetal harm was observed.
Before initiating treatment, female patients with reproductive potential should undergo a pregnancy test.
Effectibec should be used for the duration of the treatment, and at least two days following the last dose.

Lefamulin use during breastfeeding:

It is unknown if the drug will be excreted into breastmilk.
The manufacturer suggests that you avoid breastfeeding during treatment and at least two days after the last dose.
Breastfeeding women can express breastmilk and then discard it.

Dose in Kidney Disease:

Adjustment in the dose is not necessary.

Lefamulin (Xenleta) Dose in Liver disease:

IV:
- Mild to moderate impairment (Child-Pugh class A or B):
  - Adjustment in the dose is not necessary.
- Severe impairment (Child-Pugh class C):
  - 150 mg once every 24 hours.
Oral:
- Mild impairment (Child-Pugh class A):
  - Adjustment in the dose is not necessary.
- Moderate or severe impairment (Child-Pugh class B or C):
  - It is not recommended (the drug has not been studied in patients with moderate to severe liver disease).

Common Side Effects of Lefamulin (Xenleta):

Gastrointestinal:
- Diarrhea

Less Common Side Effects of Lefamulin (Xenleta):

Cardiovascular:
- Atrial Fibrillation
- Palpitations
- Prolonged QT Interval On ECG
Central Nervous System:
- Insomnia
- Headache
- Anxiety
- Drowsiness
Endocrine & Metabolic:
- Hypokalemia
- Increased Gamma-Glutamyl Transferase
Gastrointestinal:
- Nausea
- Vomiting
- Abdominal Pain
- Clostridioides Difficile Associated Diarrhea
- Constipation
- Dyspepsia
- Epigastric Discomfort
- Gastritis
- Oropharyngeal Candidiasis
Genitourinary:
- Urinary Retention
- Vulvovaginal Candidiasis
Hematologic & Oncologic:
- Anemia
- Thrombocytopenia
Hepatic:
- Increased Liver Enzymes
- Increased Serum Alanine Aminotransferase
- Increased Serum Aspartate Aminotransferase
- Increased Serum Alkaline Phosphatase
Local:
- Infusion-Site Pain
- Injection Site Phlebitis
- Injection Site Reaction
Neuromuscular & Skeletal:
- Increased Creatine Phosphokinase In Blood Specimen

Contraindications to Lefamulin (Xenleta):

Allergy reactions to lefamulin, the pleuromutilin-class drugs, or any component in the formulation Additional contraindications include tablets:
Concomitant use of CYP3A4 substrates that prolong the QT interval such as pimozide.

Warnings and precautions

Extension of QT
- QT prolongation can occur in certain patients, especially if they have a fast rate of infusion or a higher concentration.
- Do not exceed the recommended rate or concentration of infusion.
- Patients who are taking concomitant drugs, such as:
  - Antiarrhythmic drugs of class IA, such as quinidine or procainamide, are available
  - class III antiarrhythmics drugs such as amiodarone and sotalol
  - Other drugs that can prolong the QT interval include antipsychotics and moxifloxacin.
- Patients with a history QT interval prolongation, ventricular arrhythmias, including torsade-de-pointes should avoid it.
- QT interval prolongation is also possible in patients with liver and renal disease.
- Continuous ECG monitoring is recommended if the drug cannot be avoided in patients at high risk.
Superinfection
- Clostridium difficile infection (formerly Clostridium) may be a superinfection.
- Clostridium difficile infection can persist for up to two months after the last dose.
Hepatic impairment
- Patients with severe to moderate hepatic impairment should avoid oral medication.
- Patients with Child class C liver disease may need to be given the injectable formulation at a lower dosage.

Lefamulin: Drug Interaction

Risk Factor C (Monitor therapy)
Abemaciclib	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Abemaciclib.
AmLODIPine	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of AmLODIPine.
Apixaban	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Apixaban.
BCG Vaccine (Immunization)	Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization).
Benzhydrocodone	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Benzhydrocodone. Specifically, the concentration of hydrocodone may be increased.
Blonanserin	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Blonanserin.
Brexpiprazole	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Brexpiprazole. Management: The brexpiprazole dose should be reduced to 25% of usual if used together with both a moderate CYP3A4 inhibitor and a strong or moderate CYP2D6 inhibitor, or if a moderate CYP3A4 inhibitor is used in a CYP2D6 poor metabolizer.
Cannabidiol	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cannabidiol.
Cannabis	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be increased.
Clofazimine	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Codeine	CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Codeine.
CYP3A4 Inhibitors (Moderate)	May increase the serum concentration of Lefamulin. Management: Monitor for lefamulin adverse effects during coadministration of lefamulin tablets with moderate CYP3A4 inhibitors.
CYP3A4 Substrates (High risk with Inhibitors)	CYP3A4 Inhibitors (Moderate) may decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Exceptions: Alitretinoin (Systemic); Praziquantel; Trabectedin; Vinorelbine.
Deferasirox	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Dronabinol	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dronabinol.
Duvelisib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Erdafitinib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Erdafitinib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Erdafitinib	May increase the serum concentration of P-glycoprotein/ABCB1 Substrates.
Estrogen Derivatives	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Estrogen Derivatives.
Fosnetupitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
HYDROcodone	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of HYDROcodone.
Ifosfamide	CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Ifosfamide.
Imatinib	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Imatinib.
Lactobacillus and Estriol	Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol.
Larotrectinib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Levamlodipine	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Levamlodipine.
Manidipine	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Manidipine.
Meperidine	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Meperidine.
Mirodenafil	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Mirodenafil.
Naldemedine	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Naldemedine.
Nalfurafine	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Nalfurafine.
Netupitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
NiMODipine	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of NiMODipine.
OxyCODONE	CYP3A4 Inhibitors (Moderate) may enhance the adverse/toxic effect of OxyCODONE. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of OxyCODONE. Serum concentrations of the active metabolite Oxymorphone may also be increased.
Palbociclib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Pexidartinib	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pexidartinib.
Pimecrolimus	CYP3A4 Inhibitors (Moderate) may decrease the metabolism of Pimecrolimus.
QT-prolonging Agents (Highest Risk)	QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk.
Rupatadine	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Rupatadine.
Ruxolitinib	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ruxolitinib.
Salmeterol	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Salmeterol.
Sarilumab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
SAXagliptin	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of SAXagliptin.
Sildenafil	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sildenafil.
Silodosin	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Silodosin.
Siltuximab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Tamsulosin	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tamsulosin.
Tetrahydrocannabinol	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol.
Ticagrelor	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ticagrelor.
Tocilizumab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Tofacitinib	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tofacitinib.
Trabectedin	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Trabectedin.
Udenafil	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Udenafil.
Vilazodone	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vilazodone.
Vindesin	: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vindesine.
Zuclopenthixol	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zuclopenthixol.
Risk Factor D (Consider therapy modification)
Acalabrutinib	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Acalabrutinib. Management: Reduce acalabrutinib dose to 100 mg once daily with concurrent use of a moderate CYP3A4 inhibitor. Monitor patient closely for both acalabrutinib response and evidence of adverse effects with any concurrent use.
ARIPiprazole	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations.
Avanafil	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avanafil. Management: The maximum avanafil adult dose is 50 mg per 24-hour period when used together with a moderate CYP3A4 inhibitor. Patients receiving such a combination should also be monitored more closely for evidence of adverse effects.
Avapritinib	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avapritinib. Management: Avoid use of moderate CYP3A4 inhibitors with avapritinib. If this combination cannot be avoided, reduce the avapritinib dose from 300 mg once daily to 100 mg once daily.
Brigatinib	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Brigatinib. Management: Avoid concurrent use of brigatinib with moderate CYP3A4 inhibitors when possible. If such a combination cannot be avoided, reduce the dose of brigatinib by approximately 40% (ie, from 180 mg to 120 mg, from 120 mg to 90 mg, or from 90 mg to 60 mg).
Bromocriptine	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bromocriptine. Management: The bromocriptine dose should not exceed 1.6 mg daily with use of a moderate CYP3A4 inhibitor. The Cycloset brand specifically recommends this dose limitation, but other bromocriptine products do not make such specific recommendations.
Budesonide (Topical)	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Topical). Management: Per US prescribing information, avoid this combination. Canadian product labeling does not recommend strict avoidance. If combined, monitor for excessive glucocorticoid effects as budesonide exposure may be increased.
Cilostazol	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in adult patients who are also receiving moderate inhibitors of CYP3A4.
Colchicine	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Colchicine. Management: Reduce colchicine dose as directed when using with a moderate CYP3A4 inhibitor, and increase monitoring for colchicine-related toxicity. See full monograph for details. Use extra caution in patients with impaired renal and/or hepatic function.
CYP3A4 Inducers (Moderate)	May decrease the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin with moderate CYP3A4 inducers unless the benefits outweigh the risks.
CYP3A4 Inducers (Strong)	May decrease the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin with strong CYP3A4 inducers unless the benefits outweigh the risks.
Dabrafenib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects).
Dapoxetine	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dapoxetine. Management: The dose of dapoxetine should be limited to 30 mg per day when used together with a moderate inhibitor of CYP3A4.
Deflazacort	CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Deflazacort. Management: Administer one third of the recommended deflazacort dose when used together with a strong or moderate CYP3A4 inhibitor.
DOXOrubicin (Conventional)	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to moderate CYP3A4 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided.
Eletriptan	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eletriptan. Management: The use of eletriptan within 72 hours of a moderate CYP3A4 inhibitor should be avoided.
Eliglustat	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eliglustat. Management: Use should be avoided under some circumstances. See full drug interaction monograph for details.
Enzalutamide	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring.
Eplerenone	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eplerenone. Management: When used concomitantly with moderate inhibitors of CYP3A4, eplerenone dosing recommendations vary by indication and international labeling. See full drug interaction monograph for details.
Everolimus	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for most indications. See full monograph or prescribing information for specific dose adjustment and monitoring recommendations.
FentaNYL	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of FentaNYL. Management: Monitor patients closely for several days following initiation of this combination, and adjust fentanyl dose as necessary.
GuanFACINE	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of GuanFACINE. Management: Reduce the guanfacine dose by 50% when initiating this combination.
Ibrutinib	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ibrutinib. Management: When treating B-cell malignancies, decrease ibrutinib to 280 mg daily when combined with moderate CYP3A4 inhibitors. When treating graft versus host disease, monitor patients closely and reduce the ibrutinib dose as needed based on adverse reactions.
Ivacaftor	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivacaftor. Management: Ivacaftor dose reductions may be required; consult full monograph content for product-specific recommendations. No dose adjustment is needed when using ivacaftor/lumacaftor with a moderate CYP3A4 inhibitor.
Lorlatinib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences.
Lurasidone	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lurasidone. Management: Lurasidone US labeling recommends reducing lurasidone dose by half with a moderate CYP3A4 inhibitor. Some non-US labeling recommends initiating lurasidone at 20 mg/day and limiting dose to 40 mg/day; avoid concurrent use of grapefruit products.
Mitotane	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane.
Olaparib	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Olaparib. Management: Avoid use of moderate CYP3A4 inhibitors in patients being treated with olaparib, if possible. If such concurrent use cannot be avoided, the dose of olaparib should be reduced to 150 mg twice daily.
P-glycoprotein/ABCB1 Inducers	May decrease the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin with P-glycoprotein/ABCB1 inducers unless the benefits outweigh the risks.
P-glycoprotein/ABCB1 Inhibitors	May increase the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin tablets with P-glycoprotein/ABCB1 inhibitors. If concomitant use is required, monitor for lefamulin adverse effects.
Ranolazine	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ranolazine. Management: Limit the ranolazine adult dose to a maximum of 500 mg twice daily in patients concurrently receiving moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil, erythromycin, etc.).
Sirolimus	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sirolimus. Management: Monitor for increased serum concentrations of sirolimus if combined with a moderate CYP3A4 inhibitor. Lower initial sirolimus doses or sirolimus dose reductions will likely be required.
Sodium Picosulfate	Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic.
Sonidegib	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sonidegib. Management: Avoid concomitant use of sonidegib and moderate CYP3A4 inhibitors when possible. When concomitant use cannot be avoided, limit CYP3A4 inhibitor use to less than 14 days and monitor for sonidegib toxicity (particularly musculoskeletal adverse reactions).
Stiripentol	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring.
Suvorexant	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Suvorexant. Management: The recommended dose of suvorexant is 5 mg daily in patients receiving a moderate CYP3A4 inhibitor. The dose can be increased to 10 mg daily (maximum dose) if necessary for efficacy.
Tezacaftor	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tezacaftor. Management: When combined with moderate CYP3A4 inhibitors, tezacaftor/ivacaftor or elexacaftor/tezacaftor/ivacaftor should be given in the morning, every other day. Ivacaftor alone should be given in the morning, every other day on alternate days.
Tolvaptan	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tolvaptan. Management: Jynarque dose requires adjustment when used with a moderate CYP3A4 inhibitor. See labeling or full interaction monograph for specific recommendations. Use of Samsca with moderate CYP3A4 ihibitors should generally be avoided.
Triazolam	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Triazolam. Management: Consider triazolam dose reduction in patients receiving concomitant moderate CYP3A4 inhibitors.
Typhoid Vaccine	Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in patients being treated with systemic antibacterial agents. Use of this vaccine should be postponed until at least 3 days after cessation of antibacterial agents.
Ubrogepant	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 50 mg and avoid a second dose for 24 hours when used with moderate CYP3A4 inhibitors.
Venetoclax	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations.
Zanubrutinib	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zanubrutinib. Management: Decrease the zanubrutinib dose to 80 mg twice daily during coadministration with a moderate CYP3A4 inhibitor. Further dose adjustments may be required for zanubrutinib toxicities, refer to prescribing information for details.
Zopiclone	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zopiclone. Management: The starting adult dose of zopiclone should not exceed 3.75 mg if combined with a moderate CYP3A4 inhibitor. Monitor patients for signs and symptoms of zopiclone toxicity if these agents are combined.
Risk Factor X (Avoid combination)
Aprepitant	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Aprepitant.
Asunaprevir	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Asunaprevir.
BCG (Intravesical)	Antibiotics may diminish the therapeutic effect of BCG (Intravesical).
Bosutinib	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bosutinib.
Budesonide (Systemic)	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Systemic).
Cholera Vaccine	Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Management: Avoid cholera vaccine in patients receiving systemic antibiotics, and within 14 days following the use of oral or parenteral antibiotics.
Cobimetinib	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cobimetinib. Management: Avoid the concomitant use of cobimetinib and moderate CYP3A4 inhibitors. If concurrent short term (14 days or less) use cannot be avoided, reduce the cobimetinib dose to 20 mg daily.
Conivaptan	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
CYP3A4 Inhibitors (Strong)	May increase the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin tablets and strong inhibitors of CYP3A4.
Domperidone	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Domperidone. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Flibanserin	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Flibanserin.
Fosaprepitant	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Fosaprepitant.
Fusidic Acid (Systemic)	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Idelalisib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Ivabradine	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivabradine.
Lasmiditan	May increase the serum concentration of P-glycoprotein/ABCB1 Substrates.
Lemborexant	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lemborexant.
Lomitapide	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lomitapide.
Lumateperone	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lumateperone.
Naloxegol	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Naloxegol.
Neratinib	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Neratinib.
Pimozide	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pimozide.
QT-prolonging CYP3A4 Substrates	Lefamulin may enhance the QTc-prolonging effect of QTprolonging CYP3A4 Substrates. Management: Do not use lefamulin tablets with QT-prolonging CYP3A4 substrates. Lefamulin prescribing information lists this combination as contraindicated.
Simeprevir	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Simeprevir.
Ulipristal	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ulipristal. Management: This is specific for when ulipristal is being used for signs/symptoms of uterine fibroids (Canadian indication). When ulipristal is used as an emergency contraceptive, patients receiving this combination should be monitored for ulipristal toxicity.

Monitoring parameters:

Liver function tests
ECG in patients who are at risk of developing QT prolongation
Pregnancy status should be evaluated in females of reproductive potential.

How to administer Lefamulin (Xenleta)?

IV formulation:

Administer the drug by IV infusion over at least one hour.
Note:
- Prior to preparing the infusion, the Injection solution in vials should be diluted with the diluent that is provided with it.

Oral formulation:

Administer the drug at least one hour before or two hours after a meal.
Avoid crushing or chewing the tablet. Swallow the tablets with 6 to 8 ounces of water.

Mechanism of action of Lefamulin (Xenleta):

Lefamulin is a member of the. Pleuromutilin is a class of drugs.
It inhibits the production of bacterial proteins by interfering with the peptidyl transportase centre in domain V, 23s ribosomalRNA subunit 50S.
I hinders the proper positioning the transferRNA because the binding pocket of bacterial ribosomes closes around the core of the muslin for an induced fit.

Protein binding:

94.8% to 97.1%.

Metabolism:

Primarily CYP3A4.

Bioavailability:

Oral: 25%;
The bioavailability of the drug is slightly decreased when it is administered with food.

Half-life elimination:

About 8 hours (range: 3 to 20 hours);
17.5 hours when administered intravenously in patients with severe hepatic impairment.

Time to peak:

Oral: 0.88 to 2 hours.

Excretion:

IV:
- Feces: 77.3% (4.2% to 9.1% unchanged);
- urine: 15.5% (9.6% to 14.1% unchanged).
Oral:
- Feces: 88.5% (7.8% to 24.8% unchanged);
- urine: 5.3% (percentage unchanged not determined).