Lefamulin

Risk Summary

Based on findings from animal studies, lefamulin may cause fetal harm when administered to pregnant women. There are no available data on the use of lefamulin in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.

Animal studies indicate that intravenous administration of lefamulin 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 suggest treatment-related developmental delay, and malformations in rats at maternal exposures greater than 0.4 times the mean exposure in CABP patients for which the litter incidence was nonexistent in concurrent controls and rare (0 to approximately 0.3%) in historical controls. Decreased ossification was seen in fetuses at all doses in a dose-related manner, suggestive of developmental delay (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

There is a pregnancy pharmacovigilance program for lefamulin. If lefamulin is inadvertently administered during pregnancy or if a patient becomes pregnant while receiving lefamulin, healthcare providers should report lefamulin exposure by calling 1-855-5NABRIVA to enroll.

Data

Animal Data

In a prenatal and postnatal development study in rats treated from the beginning of organogenesis through lactation (Gestation Day [GD] 6 through lactation day 21), the percent of live births was reduced (87.4% compared with the concurrent control of 98.7%) in the high dose group of 100 mg/kg/day (0.9 times the mean exposure in CABP patients treated IV). Equivocal findings in that study were indicative of early post-natal mortality and apparent developmental delay that may be related to pre-natal effects.

In the rat embryo-fetal development study of IV lefamulin during organogenesis (GD 6-17), findings included late resorptions in the high-dose group and malformations (cleft palate/jaw/vertebral malformations at the mid and high doses and enlarged ventricular heart chamber with a thin ventricular wall at the high dose) for which the litter incidence was nonexistent in concurrent controls and rare in historical controls (0 to approximately 0.3%). Decreased or no ossification in a number of skeletal elements in all treated groups may indicate treatment-related developmental delay at all doses. The mean exposure at the lowest dose was approximately 0.4 times the mean exposure in CABP patients treated IV. The main human metabolite, 2R-hydroxy lefamulin, was evaluated in an embryo-fetal development study in rats after IV administration and was also associated with the same cardiac malformation seen in the above study, enlarged ventricular heart chamber with or without a thin ventricular wall (which could be associated with undetected valve or great vessel anomalies).

In the rabbit embryo-fetal development study of IV lefamulin during organogenesis (GD 6-18), low numbers of live fetuses in utero in treated groups limited evaluation of the study. Additional findings at the high dose included decreased fetal weight and decreased or no ossification of skeletal elements, which may be indicative of developmental delay. A NOAEL was not determined. The lowest dose (not fully evaluated due to fetal mortality) would correspond to a mean exposure approximately 0.1 times the mean exposure in CABP patients.

Results of animal studies indicate that lefamulin crosses the placenta and is found in fetal tissues. Following a single intravenous administration of 30 mg/kg radio-labelled lefamulin to pregnant female rats on Day 17 of gestation, radioactivity was visible in fetal tissue, with greatest concentrations measured in the placenta and fetal liver (34.3 and 8.26 mcg equivalents/g, respectively) compared to 96.6 mcg equivalents/g in the maternal liver. Radioactivity in fetal tissues generally declined rapidly, and radioactivity associated with the fetus itself was below the limit of quantification by 12 hours post-dose. Radioactivity in the placenta declined rapidly and was below the limit of quantification by 24 hours after dosing. Concentrations of radioactivity in the amniotic sac remained measurable at the final sampling time (72 hours), peaking at 6 hours post-dose. The amniotic fluid did not contain radioactivity at any time after dose administration.

Risk Summary

There are no data on the presence of lefamulin in human milk, its effects on the breastfed infant, or its effects on milk production. Animal studies indicate that lefamulin was concentrated in the milk of lactating rats (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the potential for serious adverse reactions, including QT prolongation, a woman should pump and discard human milk for the duration of treatment with lefamulin and for 2 days after the final dose.

Data

Administration of a single intravenous dose of 30 mg/kg radio-labelled lefamulin to lactating rats resulted in maximal mean concentrations of radioactivity in plasma and milk at 0.25-hour post-dose (3.29 and 10.7 mcg equivalents/g, respectively) that were markedly reduced at 24 hours post-dose (0.00663 and 0.0700 mcg equivalents/g, respectively). Milk/plasma ratios increased from 3.27 at 0.25-hour post-dose to 8.33 at 6 hours post-dose. These data indicate that pups would be exposed to lefamulin and its metabolites in maternal milk.

Long-term carcinogenicity studies have not been conducted with lefamulin.

Lefamulin did not elicit genotoxic potential in an in vivo clastogenicity assay. Valid in vitro mutagenicity assays have not been performed for lefamulin or the main human metabolite of lefamulin (2R-hydroxy lefamulin). At least six impurities have been identified to be possibly genotoxic based on chemical structure, while two others were positive in mutagenicity testing and may contribute to a total amount of genotoxic impurities that exceed the acceptable total daily intake of mutagenic impurities. However, since the duration of clinical dosing is limited to 5-7 days, the clinical implications are unknown.

In rats, there were no effects on male fertility that were considered to be related to lefamulin. Reproductive indices including mating behavior and fertility were not changed in any group in either gender at the highest dose tested (75 mg/kg/day, approximately 0.7 times the mean exposure of CABP patients treated IV, based on AUC_0-24h); that dose was the NOAEL for fertility in male rats. In females, abnormal estrous cycling and increased post-implantation loss were observed at the high dose, making the NOAEL for fertility and early embryonic development in female rats the next highest dose, 50 mg/kg/day (approximately 0.5 times the mean exposure of CABP patients treated IV).

• QT Prolongation
• Clostridium difficile-associated Diarrhea

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Lefamulin was evaluated in two clinical trials in CABP patients (Trial 1 and Trial 2). Across the two trials, a total of 641 patients were treated with lefamulin. Trial 1 (intravenous [IV] to oral dosing switch trial) enrolled 551 adult patients, 276 randomized to lefamulin (273 received at least one dose of lefamulin) and 275 randomized to moxifloxacin (273 received at least one dose of moxifloxacin). Trial 2 (oral dosing only trial) enrolled 738 adult patients, 370 randomized to lefamulin (368 received at least one dose of lefamulin) and 368 randomized to moxifloxacin (all 368 received at least one dose of moxifloxacin).

Trial 1 enrolled patients with Pneumonia Outcomes Research Team (PORT) Risk Class III-V. The mean duration of intravenous treatment was 6 days; the mean total duration of treatment was 7 days. Trial 2 enrolled patients with PORT Risk Class II-IV. The mean duration of treatment was 5 days for lefamulin and 7 days for moxifloxacin.

In Trial 1 and Trial 2 (pooled), the median age of patients treated with lefamulin was 61 (range 19-97) years; 42% of patients were 65 years or older and 18% were 75 years or older. Patients were predominantly male (58%) and white (79%) and had a median body mass index (BMI) of 26.0 (range 13.0-56.8) kg/m². Approximately 52% of lefamulin-treated patients had creatinine clearance (CrCl) <90 mL/min.

Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation

In Trial 1 and Trial 2 (pooled), serious adverse reactions occurred in 36/641 (5.6%) patients treated with lefamulin and 31/641 (4.8%) patients treated with moxifloxacin. Treatment was discontinued due to an adverse reaction in 21/641 (3.3%) patients treated with lefamulin and 21/641 (3.3%) patients treated with moxifloxacin. Death within 28 days occurred in 8/641 (1.2%) patients treated with lefamulin and 7/641 (1.1%) patients treated with moxifloxacin.

Most Common Adverse Reactions

Table 1 and Table 2 include adverse reactions occurring in ≥2% of patients receiving lefamulin in Trials 1 and 2.

Table 1. Adverse Reactions Occurring in ≥2% of Patients Receiving Lefamulin in Trial 1:

* Administration site reactions include infusion site pain, infusion site phlebitis, and injection site reaction.\
** Hepatic enzyme elevation includes alanine aminotransferase increased, aspartate aminotransferase increased, and liver function test increased.

Table 2. Adverse Reactions Occurring in ≥2% of Patients Receiving Lefamulin in Trial 2:

** Hepatic enzyme elevation includes alanine aminotransferase increased, aspartate aminotransferase increased, and liver function test increased.

Selected Adverse Reactions Occurring in Less Than 2% of Patients Receiving Lefamulin in Trials 1 and 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: 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