Schedule H

Oral, Intravenous

Form Strength

Tablet 600 mg

Injection 150 mg per vial (for IV infusion)

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India):

▶ Community-Acquired Bacterial Pneumonia (CABP) in Adults

Caused by susceptible organisms including Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, Legionella pneumophila, and Chlamydophila pneumoniae

Oral Route:

Parameter Details

Starting dose 600 mg every 12 hours

Titration Not applicable

Usual maintenance dose 600 mg every 12 hours

Maximum dose 600 mg every 12 hours (1200 mg/day)

Duration 5 days

Intravenous Route:

Parameter Details

Starting dose 150 mg IV every 12 hours

Titration Not applicable

Usual maintenance dose 150 mg IV every 12 hours

Maximum dose 150 mg IV every 12 hours (300 mg/day)

Duration 5–7 days

Infusion time Over 60 minutes

Key Clinical Notes:

• Route selection based on severity: Use IV for hospitalized or moderate-to-severe cases

• Step-down to oral therapy when clinically stable and tolerating oral intake

• May be taken with or without food (oral)

• Avoid in severe hepatic impairment

Secondary Indications – Adults Only (Off-label):

▶ Skin and Soft Tissue Infections (SSTI) including MRSA — OFF-LABEL

Parameter Details

Starting dose 600 mg oral every 12 hours OR 150 mg IV every 12 hours

Titration Not applicable

Usual maintenance dose Same as starting dose

Maximum dose 600 mg oral q12h or 150 mg IV q12h

Duration 5–7 days depending on severity

Supervision Specialist only

Evidence basis Limited observational data; not yet standard in Indian practice

PAEDIATRIC DOSING (Specialist Only)

Primary Indications:

NOT APPROVED for paediatric use in India

Parameter Recommendation

Approval status Safety and efficacy not established below 18 years

Dosing data No dosing guidelines available in Indian sources

Use consideration Only under paediatric infectious disease specialist supervision in exceptional circumstances

Secondary Indications – Paediatrics (Off-label):

Not applicable — no established off-label paediatric indications due to lack of safety data.

Age Restriction Statement:

NOT RECOMMENDED BELOW 18 YEARS except under specialist supervision with documented exceptional indication.

ESRD / Haemodialysis No dose adjustment required; not significantly removed by dialysis

Note: IV formulation contraindicated in moderate-severe hepatic impairment due to increased drug exposure and cardiac risk.

• Known hypersensitivity to lefamulin or any pleuromutilin-class antibiotic

• Severe hepatic impairment (Child-Pugh C)

• Concomitant use with CYP3A4 substrates that prolong QT interval (e.g., pimozide, cisapride, amiodarone, sotalol, quinidine)

• Known congenital QT prolongation syndrome

• History of cardiac arrhythmia or documented QT prolongation

• Concurrent use of other QT-prolonging medications (see interactions)

• Moderate hepatic impairment (Child-Pugh B) — use oral with caution; avoid IV

• Electrolyte abnormalities (hypokalaemia, hypomagnesaemia) — correct before initiating

• Elderly patients with polypharmacy

• History of Clostridioides difficile infection

Parameter Recommendation

Risk category Not formally classified in India; embryotoxicity observed in animal studies

Overall safety Not recommended; avoid especially in first trimester

Preferred alternatives Beta-lactams (amoxicillin-clavulanate), macrolides (azithromycin) if organism susceptible

When may be used Only if no alternatives available and benefit clearly outweighs risk; specialist decision

Monitoring Fetal growth surveillance if used

Parameter Recommendation

Excretion in milk Unknown; insufficient human data

Compatibility Manufacturer recommends avoiding breastfeeding during treatment and for 2 days after last dose

Preferred alternatives Amoxicillin-clavulanate, azithromycin (better safety data in lactation)

Infant monitoring GI symptoms (diarrhoea, feeding difficulties) if inadvertently exposed

Parameter Recommendation

Starting dose No specific dose change; use standard adult dosing (600 mg oral q12h or 150 mg IV q12h)

Titration Not applicable

Additional risks Increased risk of QT prolongation; drug accumulation if hepatic reserve compromised

Special considerations Polypharmacy increases interaction risk; obtain baseline ECG in patients with cardiac history or on multiple medications

Interacting Drug/Class Mechanism / Risk Recommendation

CYP3A4 substrates with narrow therapeutic index (colchicine, cyclosporine, tacrolimus, sirolimus) Lefamulin inhibits CYP3A4; increased substrate levels and toxicity Avoid combination or significantly reduce substrate dose with close monitoring

QT-prolonging agents (amiodarone, sotalol, dronedarone, moxifloxacin, haloperidol, ondansetron) Additive QT prolongation; risk of torsades de pointes Avoid combination; if unavoidable, obtain baseline and serial ECGs

Strong CYP3A4 inducers (rifampicin, phenytoin, carbamazepine, St. John's Wort) Reduced lefamulin plasma levels; potential treatment failure Avoid co-administration

P-glycoprotein substrates (digoxin) Lefamulin inhibits P-gp; increased digoxin levels Avoid or monitor digoxin levels closely

Interacting Drug/Class Mechanism / Risk Recommendation

Moderate CYP3A4 inhibitors (diltiazem, verapamil, erythromycin) May increase lefamulin exposure Monitor for adverse effects; no dose adjustment typically required

Statins metabolized by CYP3A4 (simvastatin, atorvastatin) Increased statin levels; myopathy risk Use lowest effective statin dose; monitor for muscle symptoms

Warfarin Enhanced anticoagulant effect reported Monitor INR closely during and after lefamulin therapy

Oral contraceptives Potential for reduced efficacy (CYP3A4 interaction) Advise additional contraceptive measures during treatment

• Diarrhoea

• Nausea

• Vomiting

• Elevated hepatic transaminases (ALT/AST)

• Injection site reactions (IV formulation)

• Headache

• Hypokalaemia

Adverse Effect Notes

QTc prolongation May lead to torsades de pointes; requires immediate discontinuation if significant prolongation detected

Clostridioides difficile-associated diarrhoea (CDAD) May occur during or after therapy; discontinue and initiate specific treatment

Hepatotoxicity Rare but can be severe; discontinue if significant transaminase elevation or clinical hepatitis

Severe hypersensitivity reactions Including angioedema and severe rash; requires immediate discontinuation

During therapy Clinical response; monitor for GI adverse effects; repeat LFTs at day 3–4 in patients with hepatic risk factors

If QT concern Serial ECGs during therapy

Long-term Not indicated for prolonged use; short-course therapy only

• Xenleta (Nabriva/Themis Medicare — licensed import)

Note: Limited availability; primarily through hospital-based procurement and specialty channels. Domestic generic manufacturing not yet established.

NLEM Status: Not included in NLEM 2022; not under price control

Availability: High cost limits use to tertiary care settings; not widely stocked in retail pharmacies

• Valuable alternative for CABP when atypical pathogens suspected and beta-lactam/macrolide resistance or allergy precludes standard agents

• Covers both typical and atypical respiratory pathogens — useful when causative organism unknown but atypical coverage desired

• Check baseline ECG in patients with cardiac history or on QT-prolonging medications before initiating therapy

• Avoid IV formulation in moderate hepatic impairment — switch to oral if patient can tolerate

• Not a first-line agent in Indian practice — reserve for resistant or atypical pneumonia where other options unsuitable

• Short 5-day oral course offers compliance advantage over longer antibiotic regimens

lefamulin; pleuromutilin; CABP; pneumonia; atypical pathogens; QT-prolongation; hepatic-caution; CYP3A4-inhibitor; antibiotic; Mycoplasma; Legionella

RxIndia v1.0 — 28 May 2025

• CDSCO import license documentation for lefamulin

• NFI (National Formulary of India), 2021

• AIIMS Antimicrobial Policy 2023

• API Textbook of Medicine

• ICMR-AMR Guidelines 2023

• Goodman & Gilman's The Pharmacological Basis of Therapeutics (supportive pharmacology)

• NLEM 2022: Lefamulin NOT LISTED

• IP/NFI: NOT LISTED in Indian Pharmacopoeia

• LEAP 1 & LEAP 2 Phase III trials (international RCTs — used for supportive efficacy data only)