Lefamulin

Chemical formula: C₂₈H₄₅NO₅S  Molecular mass: 507.73 g/mol  PubChem compound: 25185057

Interactions

Lefamulin interacts in the following cases:

Renal failure requiring dialysis

Lefamulin should be used with caution in patients with renal failure who require dialysis because metabolic disturbances associated with renal failure may lead to QT prolongation.

Moderate or severe hepatic impairment

Patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment have reduced lefamulin protein binding compared to healthy subjects or subjects with mild (Child-Pugh Class A) hepatic impairment. Treatment should be initiated in patients with moderate or severe hepatic impairment only after a careful benefit/risk evaluation, due to possible adverse reactions related to higher free concentrations of lefamulin, including prolongation of the QTcF interval. Patients should be monitored closely during treatment.

Ethinylestradiol

Use with caution.

Possible mechanism of interaction: inhibition of CYP3A4.

Metformin

Caution is recommended. Co-administration with lefamulin may lead to higher exposures of metformin. Patients should be monitored.

Possible mechanism of interaction: inhibition of MATE, OCT1, OCT2.

Midazolam

Caution is recommened. when co-administered with oral lefamulin. Consider dosage adjustment of midazolam.

No dose adjustment required when co-administered with intravenous lefamulin.

Possible mechanism of interaction: inhibition of CYP3A4.

Rosuvastatin, atorvastatin, lovastatin, pravastatin

Use with caution.

Possible mechanism of interaction: inhibition of CYP3A, BCRP, OATP1.

Zolpidem

Monitor for adverse reactions during co-administration with lefamulin. Consider dosage adjustment of zolpidem.

Possible mechanism of interaction: inhibition of CYP3A4.

Mild, moderate, or severe cirrhosis

Lefamulin should be used with caution in patients with mild, moderate, or severe cirrhosis because metabolic disturbances associated with hepatic insufficiency may lead to QT prolongation.

Pregnancy

There are no data from the use of lefamulin in pregnant women. Studies in animals have shown increased incidence of stillbirth. Animal studies are insufficient with respect to embryo-foetal development. Lefamulin is not recommended during pregnancy.

Nursing mothers

It is unknown whether lefamulin/metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of lefamulin/metabolites in milk. A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with lefamulin.

Carcinogenesis, mutagenesis and fertility

Women of childbearing potential

Women of childbearing potential should use effective contraception during treatment with lefamulin. Women taking oral contraceptives should use an additional barrier method of contraception.

Fertility

The effects of lefamulin on fertility in humans have not been studied.

Lefamulin caused no impairment of fertility or reproductive performance in rats.

Effects on ability to drive and use machines

Lefamulin has no influence on the ability to drive and use machines.

Adverse reactions


Summary of the safety profile

The most frequently reported adverse reactions are administration site reactions (7%), diarrhoea (7%), nausea (4%), vomiting (2%), hepatic enzyme elevation (2%), headache (1%), hypokalaemia (1%), and insomnia (1%).

Administration site reactions apply to intravenous administration and led to treatment discontinuation in <1%. Gastrointestinal disorders were predominantly associated with the oral formulation of lefamulin and led to treatment discontinuation in <1%.

The most frequently reported serious adverse reaction is atrial fibrillation (<1%).

Tabulated list of adverse reactions

Based on pooled data from Phase 3 trials for both intravenous and oral formulations, the following adverse reactions have been identified with lefamulin. Adverse reactions are classified according to System Organ Class and frequency. Frequency categories are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from the available data).

Frequency of adverse reactions by system organ class from clinical trials:

System organ class Common Uncommon
Infections and infestations Clostridioides difficile colitis
Oropharyngeal candidiasis
Vulvovaginal mycotic infection
Blood and lymphatic system
disorders
 Anaemia
Thrombocytopenia
Metabolism and nutrition
disorders
Hypokalaemia 
Psychiatric disorders Insomnia Anxiety
Nervous system disorders Headache Dizziness
Somnolence
Cardiac disorders Electrocardiogram QT
prolonged
Atrial fibrillation
Palpitations
Respiratory, thoracic and
mediastinal disorders
 Oropharyngeal pain
Gastrointestinal disorders Diarrhoea
Nausea
Vomiting
Abdominal pain
Abdominal pain upper
Constipation
Dyspepsia
Epigastric discomfort
Gastritis
Gastritis erosive
Hepatobiliary disorders Alanine aminotransferase
increased*
Aspartate aminotransferase
increased*
Alkaline phosphatase
increased
Gamma-glutamyltransferase
increased
Renal and urinary disorders Urinary retention
General disorders and
administration site conditions
Infusion site pain
Infusion site phlebitis
Infusion site erythema
Infusion site bruising
Infusion site coldness
Investigations Creatinine phosphokinase
increased

* In Phase 3 trials (pooled data for intravenous and oral formulations), post-baseline alanine aminotransferase values >3x and >5x ULN occurred in 5% and 2% of lefamulin patients compared with 5% and 1% of moxifloxacin patients. Post-baseline aspartate aminotransferase values >3x and >5x ULN occurred in 4% and 1% of lefamulin patients compared with 2% and 1% of moxifloxacin patients. Those affected were asymptomatic with reversible clinical laboratory findings that typically peaked within the first week of lefamulin dosing. No lefamulin patient met Hy’s Law criteria.

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