Omadacycline

Risk Summary

Omadacycline, like other tetracycline-class antibacterial drugs, may cause discoloration of deciduous teeth and reversible inhibition of bone growth when administered during the second and third trimester of pregnancy.

The limited available data of omadacycline use in pregnant women is insufficient to inform drug associated risk of major birth defects and miscarriages. Animal studies indicate that administration of omadacycline during the period of organogenesis resulted in fetal loss and/or congenital malformations in pregnant rats and rabbits at 7 times and 3 times the mean AUC exposure, respectively, of the clinical intravenous dose of 100-mg and the oral dose of 300-mg. Reductions in fetal weight occurred in rats at all administered doses (see Data). In a fertility study, administration to rats during mating and early pregnancy resulted in embryo loss at 20 mg/kg/day; systemic exposure based on AUC was approximately equal to the clinical exposure level. Results of studies in rats with omadacycline have shown tooth discoloration.

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 15-20%.

Data

Animal Data

Intravenous infusion of omadacycline to pregnant rats during organogenesis (gestation days 6-17) at doses of 5 to 80 mg/kg/day resulted in maternal lethality at 80 mg/kg/day. Increased embryo-fetal lethality and fetal malformations (whole body edema) occurred at 60 mg/kg/day (7 times the clinical AUC), dose-dependent reductions in fetal body weight occurred at all doses, and delayed skeletal ossification occurred at doses as low as 10 mg/kg/day (Systemic exposure based on AUC at a similar dose in unmated female rats in a separate study was approximately half the clinical exposure). In pregnant rabbits, intravenous infusion of 5, 10 or 20 mg/kg/day during organogenesis (gestation days 7-18) resulted in maternal lethality and body weight loss at 20 mg/kg/day. Embryo-fetal lethality, congenital malformations of the skeleton, and reduced fetal weight also occurred at 20 mg/kg/day (7 times the clinical AUC). Cardiac and lung malformations were present in dose-related incidence at 10 and 20 mg/kg/day. The fetal no-adverse-effect-level in the rabbit embryo-fetal development study was 5 mg/kg/day, at approximately 1.2 times the clinical steady state AUC.

Intravenous infusion of omadacycline to pregnant and lactating rats at doses of 7.5, 15 and 30 mg/kg/day did not adversely affect survival, growth (other than lower pup body weights and/or gains at the high dose that were only statistically significant at sporadic intervals), postnatal development, behavior, or reproductive capability of offspring at maternal doses up to 30 mg/kg/day (approximately equivalent to 3 times the IV clinical dose of 100 mg/day, based on doses normalized for total body surface area), the highest dose tested, although dosing was discontinued early in a number of animals in this group due to injection site intolerance.

Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity also has been noted in animals treated early in pregnancy.

Risk Summary

There is no information on the presence of omadacycline in human milk, the effects on the breastfed infant or the effects on milk production. Tetracyclines are excreted in human milk; however, the extent of absorption of tetracyclines, including omadacycline, by the breastfed infant is not known. Because there are other antibacterial drug options available to treat CABP and ABSSSI in lactating women and because of the potential for serious adverse reactions, including tooth discoloration and inhibition of bone growth, advise patients that breastfeeding is not recommended during treatment with omadacycline and for 4 days (based on half-life) after the last dose.

Carcinogenesis

Carcinogenicity studies with omadacycline have not been conducted. However, there has been evidence of oncogenic activity in rats in studies with the related antibacterial drugs, oxytetracycline (adrenal and pituitary tumors), and minocycline (thyroid tumors).

Mutagenesis

Omadacycline was positive for clastogenicity and aneugenicity in an in vitro chromosome aberration assay in Chinese hamster ovary (CHO) cells and for mutagenicity in an in vitro forward mutation assay in mouse lymphoma cells. These effects were seen in the presence of metabolizing enzymes.

Omadacycline was negative in a chromosomal aberration test in Chinese hamster V79 cells and in vivo micronucleus assays administered intraperitoneally to ICR mice or intravenously to HanRcc: WIST rats.

Impairment of Fertility

Omadacycline administration to male rats in a fertility study caused reduced sperm counts and sperm motility at 20-mg/kg/day (approximately 1.3 times clinical systemic exposure, based on AUC in a separate study in rats at a similar dose), but had no effect on male fertility parameters. In general toxicity studies, inhibition of spermatogenesis occurred after administration of 45-mg/kg/day omadacycline (6 to 8 times the clinical AUC exposure) for 37 days or longer, but not at lower doses (15-mg/kg/day, ≤2 times clinical AUC exposure) or shorter treatment periods (4 weeks or less). In female rats, fertility was reduced at the 20-mg/kg/day dose (approximately equivalent to human exposures in a separate study in unmated females), characterized by reduced ovulation and increased embryonic loss when treatment occurred from before mating through early pregnancy.

• Mortality Imbalance in Patients with Community-Acquired Bacterial Pneumonia
• Tooth Development and Enamel Hypoplasia
• Inhibition of Bone Growth
• Hypersensitivity Reactions
• Tetracycline Class Effects

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.

Overview of the Safety Evaluation of Omadacycline

Omadacycline was evaluated in three Phase 3 clinical trials (Trial 1, Trial 2 and Trial 3). These trials included a single Phase 3 trial in CABP patients (Trial 1) and two Phase 3 trials in ABSSSI patients (Trial 2 and Trial 3). Across all Phase 3 trials, a total of 1073 patients were treated with omadacycline (382 patients in Trial 1 and 691 in Trials 2 and 3 of which 368 patients were treated with only oral omadacycline.

Clinical Trial Experience in Patients with Community-Acquired Bacterial Pneumonia

Trial 1 was a Phase 3 CABP trial that enrolled 774 adult patients, 386 randomized to omadacycline (382 received at least one dose of omadacycline and 4 patients did not receive the study drug) and 388 randomized to moxifloxacin (all 388 received at least one dose of moxifloxacin). The mean age of patients treated with omadacycline was 61 years (range 19 to 97 years) and 42% were greater than or equal to 65 years of age. Overall, patients treated with omadacycline were predominantly male (53.7%), white (92.4%), and had a mean body mass index (BMI) of 27.3 kg/m². Approximately 47% of omadacycline treated patients had CrCl <90 ml/min. Patients were administered an IV to oral switch dosage regimen of omadacycline. The total treatment duration was 7 to 14 days. Mean duration of IV treatment was 5.7 days and mean total duration of treatment was 9.6 days in both treatment arms.

Imbalance in Mortality

In Trial 1, eight deaths (2%) occurred in 382 patients treated with omadacycline as compared to four deaths (1%) in 388 patients treated with moxifloxacin. All deaths, in both treatment arms, occurred in patients >65 years of age. The causes of death varied and included worsening and/or complications of infection and underlying conditions. The cause of the mortality imbalance has not been established.

Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation

In Trial 1, a total of 23/382 (6.0%) patients treated with omadacycline and 26/388 (6.7%) patients treated with moxifloxacin experienced serious adverse reactions.

Discontinuation of treatment due to any adverse reactions occurred in 21/382 (5.5%) patients treated with omadacycline and 27/388 (7.0%) patients treated with moxifloxacin.

Most Common Adverse Reactions

Table 1 lists the most common adverse reactions occurring in ≥2% of patients receiving omadacycline in Trial 1.

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

Clinical Trials Experience in Patients with Acute Bacterial Skin and Skin Structure Infections

Trial 2 was a Phase 3 ABSSSI trial that enrolled 655 adult patients, 329 randomized to omadacycline and 326 randomized to linezolid. Trial 3 was a Phase 3 ABSSSI trial that enrolled 735 adult patients, 368 randomized to omadacycline and 367 randomized to linezolid.

In Trial 2 (IV to oral switch trial), the mean age of patients treated with omadacycline was 47 years (range 19 to 88). Overall, patients treated with omadacycline were predominantly male (62.8%), white (91.0%) and had a mean BMI of 28 kg/m².

In Trial 3 (oral only trial), the mean age of patients was 43 years (range 18 to 86). Patients treated with omadacycline were predominantly male (65.8%), white (88.9%), and had a mean BMI of 27.9 kg/m².

In Trials 2 and 3, approximately 12% of omadacycline treated patients had CrCl <90 ml/min. Overall, the mean and median calculated lesion area was similar across both trials. Trial 2 required at least 3 days of IV treatment followed by switch to oral regimen based on physician’s discretion. Mean duration of IV treatment in Trial 2 was 4 days and mean total duration of treatment was 9 days in both treatment arms. In Trial 3, only oral therapy was administered, and mean total duration of treatment was 8 days in both treatment arms. The median days on treatment in the pooled ABSSSI trials was 9 days for both omadacycline and linezolid.

Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation

In the pooled ABSSSI trials, serious adverse reactions occurred in 16/691 (2.3%) of patients treated with omadacycline and 13/689 (1.9%) of patients treated with comparator. Discontinuation of treatment due to adverse events occurred in 12 (1.7%) omadacycline treated patients, and 10 (1.5%) comparator treated patients. There was 1 death (0.1%) reported in omadacycline treated patients and 3 deaths (0.4%) reported in linezolid patients in ABSSSI trials.

Most Common Adverse Reactions

Table 2 includes the most common adverse reactions occurring in ≥2% of patients receiving Omadacycline in Trials 2 and 3.

Table 2. Adverse Reactions Occurring in ≥2% of Patients Receiving Omadacycline in Pooled Trials 2 and 3:

* In Trial 2, which included IV to oral dosing of omadacycline, 4 0 (12%) patients experienced nausea and 17 (5%) patients experienced vomiting in omadacycline treatment group as compared to 32 (10%) patients experienced nausea and 16 (5%) patients experienced vomiting in the comparator group. One patient (0.3%) in the omadacycline group discontinued treatment due to nausea and vomiting. In Trial 3, which included the oral loading dose of omadacycline, 111 (30%) patients experienced nausea and 62 (17%) patients experienced vomiting in omadacycline treatment group as compared to 28 (8%) patients experienced nausea and 11 (3%) patients experienced vomiting in the linezolid group. One patient (0.3%) in the omadacycline group discontinued treatment due to nausea and vomiting
^† Infusion site extravasation, pain, erythema, swelling, inflammation, irritation, peripheral swelling and skin induration.

Selected Adverse Reactions Occurring in Less Than 2% of Patients Receiving Omadacycline in Trials 1, 2 and 3

The following selected adverse reactions were reported in omadacycline-treated patients at a rate of less than 2% in Trials 1, 2 and 3.

Cardiovascular System Disorders: tachycardia, atrial fibrillation

Blood and Lymphatic System Disorders: anemia, thrombocytosis

Ear and Labyrinth Disorders: vertigo

Gastrointestinal Disorders: abdominal pain, dyspepsia

General Disorders and Administration Site Conditions: fatigue

Immune System Disorders: hypersensitivity

Infections and Infestations: oral candidiasis, vulvovaginal mycotic infection

Investigations: creatinine phosphokinase increased, bilirubin increased, lipase increased, alkaline phosphatase increased

Nervous System Disorders: dysgeusia, lethargy

Respiratory, Thoracic, and Mediastinal disorders: oropharyngeal pain

Skin and Subcutaneous Tissue Disorders: pruritus, erythema, hyperhidrosis, urticaria