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Omadacycline Injection and Tablet

TABLE OF CONTENTS

1. DESCRIPTION 8. USE IN SPECIFIC POPULATIONS
2. INDICATIONS AND USAGE 9. OVERDOSAGE
3. DOSAGE AND ADMINISTRATION 10. MECHANISM OF ACTION
4. CONTRAINDICATIONS 11. PHARMACODYNAMICS
5. WARNINGS AND PRECAUTIONS 12. PHARMACOKINETICS
6. ADVERSE REACTIONS 13. HOW SUPPLIED/STORAGE AND HANDLING
7. DRUG INTERACTIONS

 

1. DESCRIPTION

Omadacycline tosylate is an aminomethylcycline which is a semisynthetic derivative of the tetracycline class of antibacterial drugs, for intravenous or oral administration. The chemical name of omadacycline tosylate is (4S,4aS,5aR,12aS)-4,7-bis(dimethylamino)-9-(2,2- dimethylpropylaminomethyl)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene- 2-carboxamide, 4-methylbenzenesulfonate. The following represents the chemical structure of omadacycline tosylate:

Empirical formula: C36H48N4O10S

Molecular weight: 728.9 g/mol (monotosylate salt)

Omadacycline for injection is a yellow to dark orange sterile lyophilized powder. Each vial of omadacycline for injection contains 100 mg of omadacycline (equivalent to 131 mg omadacycline tosylate). Inactive ingredients: Sucrose (100 mg).

Omadacycline tablets for oral administration are yellow film coated tablets containing 150 mg of omadacycline (equivalent to 196 mg omadacycline tosylate), and the following inactive ingredients: Colloidal silicon dioxide, crospovidone, glycerol monocaprylocaprate, iron oxide yellow, lactose monohydrate, microcrystalline cellulose, polyvinyl alcohol, sodium bisulfite, sodium lauryl sulfate, sodium stearyl fumarate, talc, and titanium dioxide.

2. INDICATIONS AND USAGE

2.1 Community-Acquired Bacterial Pneumonia (CABP)

Omadacycline is indicated for the treatment of adult patients with community-acquired bacterial pneumonia (CABP) caused by the following susceptible microorganisms: Streptococcus pneumoniae, Staphylococcus aureus (methicillin-susceptible isolates), Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydophila pneumoniae.

2.2 Acute Bacterial Skin and Skin Structure Infections (ABSSSI)

Omadacycline is indicated for the treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSI) caused by the following susceptible microorganisms: Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Staphylococcus lugdunensis, Streptococcus pyogenes, Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Enterococcus faecalis, Enterobacter cloacae, and Klebsiella pneumoniae.

2.3 Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of omadacycline and other antibacterial drugs, omadacycline should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

3. DOSAGE AND ADMINISTRATION

3.1 Important Administration Instructions

Omadacycline for Injection: Do NOT administer omadacycline for injection with any solution containing multivalent cations, e.g., calcium and magnesium, through the same intravenous line [see Drug Interactions (7.2)]. Co-infusion with other medications has not been studied [see Dosage and Administration (3.5)].

Omadacycline Tablets: Fast for at least 4 hours and then take with water. After oral dosing, no food or drink (except water) is to be consumed for 2 hours and no dairy products, antacids, or multivitamins for 4 hours [see Drug Interactions (7.2) and Clinical Pharmacology].

3.2 Dosage in Adults with Community-Acquired Bacterial Pneumonia (CABP)

For treatment of adults with CABP the recommended dosage regimen of omadacycline is described in Table 1 below. Use omadacycline for injection administered by intravenous infusion for the loading dose in CABP patients.

Table 1: Dosage of Omadacycline in Adult CABP Patients

3.3 Dosage in Adults with Acute Bacterial Skin Structure and Skin Infections (ABSSSI)

For treatment of adults with ABSSSI, the recommended dosage regimen of omadacycline is described in Table 2 below. Use omadacycline for injection administered by intravenous infusion or omadacycline tablets orally administered for the loading dose in ABSSSI patients.

Table 2: Dosage of Omadacycline in Adult ABSSSI Patients

3.4 Dosage Adjustments in Patients with Renal or Hepatic Impairment

No dosage adjustment is warranted in patients with renal or hepatic impairment [see Clinical Pharmacology].

3.5 Preparation and Administration of Omadacycline for Injection Intravenous Solution

Reconstitution and Dilution:

1) Omadacycline must be reconstituted and then further diluted under aseptic conditions. To prepare the required dose for intravenous infusion, reconstitute and dilute the appropriate number of vials, as determined from Table 3 below.

2) Reconstitute each 100 mg vial of omadacycline with 5 mL of Sterile Water for Injection.

3) Gently swirl the contents and let the vial stand until the cake has completely dissolved and any foam disperses. Do not shake the vial.

4) The reconstituted omadacycline solution should be yellow to dark orange in color; if not, the solution should be discarded. Visually inspect the reconstituted omadacycline solution for particulate matter and discoloration prior to further dilution and administration. If necessary, invert the vial to dissolve any remaining powder and swirl gently to prevent foaming.

5) Immediately (within 1 hour), withdraw 5 mL or 10 ml of the reconstituted solution and further dilute to a 100 mL (nominal volume) of 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP, bag for injection. The concentration of the final diluted infusion solution will either be 1 mg/mL or 2 mg/mL in accordance with Table 3 below. Discard any unused portion of the reconstituted solution.

6) Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Table 3: Preparation of Omadacycline Intravenous Infusion

Storage of the Diluted Infusion Solution

The omadacycline diluted infusion solution may be used within 24 hours at room temperature (less than or equal to 25°C) or within 48 hours when refrigerated (2°C to 8°C). When storing the infusion solution in the refrigerator, the infusion bag should be removed from the refrigerator and incubated in a vertical position at room temperature 60 minutes before use. Do not freeze.

Administration

After reconstitution and dilution, administer omadacycline by intravenous infusion, using a total infusion time of 60 minutes for a 200-mg dose, or a total infusion time of 30 minutes for a 100-mg dose [see Dosage and Administration (3.2, 3.3)].

Administer omadacycline intravenously through a dedicated line or through a Y-site. If the same intravenous line is used for sequential infusion of several drugs, the line should be flushed with 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP, before and after infusion of omadacycline. The compatibility of omadacycline with other drugs and infusion solutions other than 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP has not been established.

4. CONTRAINDICATIONS

Omadacycline is contraindicated in patients with known hypersensitivity to omadacycline or tetracycline-class antibacterial drugs, or to any of the excipients [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)].

5. WARNINGS AND PRECAUTIONS

5.1 Mortality Imbalance in Patients with Community-Acquired Bacterial Pneumonia

Mortality imbalance was observed in the CABP clinical trial with eight deaths (2%) occurring in patients treated with omadacycline compared to four deaths (1%) in patients treated with moxifloxacin. The cause of the mortality imbalance has not been established.

All deaths, in both treatment arms, occurred in patients > 65 years of age; most patients had multiple comorbidities [see Use in Specific Populations (8.5)]. The causes of death varied and included worsening and/or complications of infection and underlying conditions. Closely monitor clinical response to therapy in CABP patients, particularly in those at higher risk for mortality [see Adverse Reactions (6.1)].

5.2 Tooth Discoloration and Enamel Hypoplasia

The use of omadacycline during tooth development (last half of pregnancy, infancy, and childhood up to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). This adverse reaction is more common during long-term use of the tetracycline class drugs, but it has been observed following repeated short-term courses. Enamel hypoplasia has also been reported with tetracycline class drugs. Advise the patient of the potential risk to the fetus if omadacycline is used during the second or third trimester of pregnancy [see Use in Specific Populations (8.1, 8.4)].

5.3 Inhibition of Bone Growth

The use of omadacycline during the second and third trimester of pregnancy, infancy and childhood up to the age of 8 years may cause reversible inhibition of bone growth. All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in premature infants given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued. Advise the patient of the potential risk to the fetus if omadacycline is used during the second or third trimester of pregnancy [see Use in Specific Populations (8.1, 8.4)].

5.4 Hypersensitivity Reactions

Hypersensitivity reactions have been reported with omadacycline [see Adverse Reactions (6.1)]. Life-threatening hypersensitivity (anaphylactic) reactions have been reported with other tetracycline-class antibacterial drugs. Omadacycline is structurally similar to other tetracycline-class antibacterial drugs and is contraindicated in patients with known hypersensitivity to tetracycline-class antibacterial drugs [see Contraindications (4)]. Discontinue omadacycline if an allergic reaction occurs.

5.5 Clostridium difficile-Associated Diarrhea

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

5.6 Tetracycline Class Effects

Omadacycline is structurally similar to tetracycline-class of antibacterial drugs and may have similar adverse reactions. Adverse reactions including photosensitivity, pseudotumor cerebri, and anti-anabolic action which has led to increased BUN, azotemia, acidosis, hyperphosphatemia, pancreatitis, and abnormal liver function tests, have been reported for other tetracycline-class antibacterial drugs, and may occur with omadacycline. Discontinue omadacycline if any of these adverse reactions are suspected.

5.7 Development of Drug-Resistant Bacteria

Prescribing omadacycline in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria [see Indications and Usage (2.3)].

6. ADVERSE REACTIONS

The following clinically significant adverse reactions are described in greater detail in the Warnings and Precautions section of labeling:

 Mortality Imbalance in Patients with Community-Acquired Bacterial Pneumonia [see Warnings and Precautions (5.1)]

 Tooth Development and Enamel Hypoplasia [see Warnings and Precautions (5.2)]

 Inhibition of Bone Growth [see Warnings and Precautions (5.3)]

 Hypersensitivity Reactions [see Warnings and Precautions (5.4)]

 Tetracycline Class Effects [see Warnings and Precautions (5.6]

6.1 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 [see Warnings and Precautions (5.1)].

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

Table 4: 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 5 includes the most common adverse reactions occurring in ≥2% of patients receiving omadacycline in Trials 2 and 3.

Table 5: 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, 40 (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

7. DRUG INTERACTIONS

7.1 Anticoagulant Drugs

Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage while also taking omadacycline.

7.2 Antacids and Iron Preparations

Absorption of oral tetracyclines, including omadacycline, is impaired by antacids containing aluminum, calcium, or magnesium, bismuth subsalicylate, and iron containing preparations [see Dosage and Administration (3.1)].

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

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 [see Warnings and Precautions (5.2, 5.3), Data, Use in Specific Populations (8.4)].

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 [see Nonclinical Toxicology]. 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.

8.2 Lactation

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.

8.3 Females and Males of Reproductive Potential

Contraception

Females

Omadacycline may produce embryonic or fetal harm [see Use in Specific Populations (8.1)]. Advise patients to use an acceptable form of contraception while taking omadacycline.

Infertility

Males

In rat studies, injury to the testis and reduced sperm counts and motility occurred in male rats after treatment with omadacycline [see Nonclinical Toxicology (13.1)].

Females

In rat studies, omadacycline affected fertility parameters in female rats, resulting in reduced ovulation and increased embryonic loss at intended human exposures [see Nonclinical Toxicology].

8.4 Pediatric Use

Safety and effectiveness of omadacycline in pediatric patients below the age of 18 years have not been established.

Due to the adverse effects of the tetracycline-class of drugs, including omadacycline on tooth development and bone growth, use of omadacycline in pediatric patients less than 8 years of age is not recommended [see Warnings and Precautions (5.1, 5.2)]

8.5 Geriatric Use

Of the total number of patients who received omadacycline in the Phase 3 clinical trials (n=1073), 200 patients were ≥ 65 years of age, including 92 patients who were ≥75 years of age. In Trial 1, numerically lower clinical success rates at early clinical response (ECR) timepoint for omadacyclinetreated and moxifloxacin-treated patients (75.5% and 78.7%, respectively) were observed in CABP patients ≥ 65 years of age as compared to patients <65 years of age (85.2% and 86.3%, respectively). Additionally, all deaths in the CABP trial occurred in patients >65 years of age [see Adverse Reactions (6.1)].

No significant difference in omadacycline exposure was observed between healthy elderly subjects and younger subjects following a single 100-mg IV dose of omadacycline [see Clinical Pharmacology].

8.6 Hepatic Impairment

No dose adjustment of omadacycline is warranted in patients with mild, moderate, or severe hepatic insufficiency (Child-Pugh classes A, B, or C) [see Clinical Pharmacology].

8.7 Renal Impairment

No dose adjustment of omadacycline is warranted in patients with mild, moderate, or severe renal impairment, including patients with end stage renal disease who are receiving hemodialysis [see Clinical Pharmacology].

9. OVERDOSAGE

No specific information is available on the treatment of overdosage with omadacycline. Following a 100 mg single dose intravenous administration of omadacycline, 8.9% of dose is recovered in the dialysate.

10. MECHANISM OF ACTION

Omadacycline is an antibacterial drug.

Mechanism of Action

Omadacycline is an aminomethylcycline antibacterial within the tetracycline class of antibacterial drugs. Omadacycline binds to the 30S ribosomal subunit and blocks protein synthesis. Omadacycline is active in vitro against Gram positive bacteria expressing tetracycline resistance active efflux pumps (tet K and tet L) and ribosomal protection proteins (tet M). In general, omadacycline is considered bacteriostatic; however, omadacycline has demonstrated bactericidal activity against some isolates of S. pneumoniae and H. influenzae.

Resistance

The following in vitro data are available, but their clinical significance is unknown. Omadacycline was active in vitro against Gram positive bacteria that carried ribosomal protection genes (tet M) and efflux genes (tet K and tet L), and in Enterobactericeae that carried the tet B efflux gene. Additionally, omadacycline was active against some S. aureus, S. pneumoniae, and H. influenzae strains carrying macrolide resistance genes (erm A, B and/or C), or ciprofloxacin resistance genes (gyrA and parC) and beta-lactamase positive H. influenzae.

Interaction with Other Antimicrobials

In vitro studies have not demonstrated antagonism between omadacycline and other commonly used antibacterials (ampicillin, ceftazidime, ceftriaxone, imipenem, piperacillin/tazobactam, gentamicin, vancomycin, daptomycin, linezolid).

Antimicrobial Activity

Omadacycline has been shown to be active against the following bacteria, both in vitro and in clinical infections [see Indications and Usage (2.1, 2.2)].

Community-Acquired Bacterial Pneumonia (CABP)

Gram-Positive bacteria

Streptococcus pneumoniae

Staphylococcus aureus (methicillin-susceptible isolates)

Gram-Negative bacteria

Haemophilus influenzae

Haemophilus parainfluenzae

Klebsiella pneumoniae

Other microorganisms

Chlamydophila pneumoniae

Legionella pneumophila

Mycoplasma pneumoniae

Acute Bacterial Skin and Skin Structure Infections (ABSSSI)

Gram-Positive bacteria

Enterococcus faecalis

Staphylococcus aureus (methicillin-susceptible and -resistant isolates)

Staphylococcus lugdunensis

Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus)

Streptococcus pyogenes

Gram-Negative bacteria

Enterobacter cloacae

Klebsiella pneumoniae

At least 90% of isolates of the following microorganisms exhibit an in-vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for omadacycline. However, the safety and effectiveness of omadacycline in treating clinical infections due to these microorganisms have not been established in adequate and well controlled clinical trials.

Gram-Positive bacteria

Enterococcus faecium (vancomycin-susceptible and -resistant isolates)

Streptococcus agalactiae

Gram-Negative bacteria

Enterobacter aerogenes

Escherichia coli

Citrobacter freundii

Citrobacter koseri

Klebsiella oxytoca

Moraxella catarrhalis

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

11. PHARMACODYNAMICS

Cardiac Electrophysiology

Based on the nonclinical and clinical data, including electrocardiogram evaluation in the phase 3 clinical trials, one of which had moxifloxacin as a control group, no clinically relevant QTc prolongation was observed at the maximum recommended dose of omadacycline.

Cardiac Physiology-Increase in Heart Rate

In phase 1 studies conducted in healthy volunteers, transient dose-dependent increases in heart rate have been observed following administration of single and multiple doses of omadacycline. The clinical implication of this finding is unknown [see Adverse Reactions (6.1)].

In a standard radiolabeled ligand binding assays, omadacycline was shown to inhibit binding of H-scopolamine to the M2 subtype of the muscarinic acetylcholine receptor. In the heart, muscarinic M2 receptors serve as mediators of the parasympathetic input that normally is received via the vagus nerve and stimulation of the receptor increases membrane potassium conductance through the acetylcholine-dependent channel, which slows depolarization and reduces pacemaker activity in the sinoatrial node.

12. PHARMACOKINETICS

The pharmacokinetic parameters of omadacycline after single and multiple oral and intravenous doses are summarized in Table 6.

Table 6: Pharmacokinetic (PK) Parameters of Omadacycline in Healthy Adult Subjects

a All PK parameters presented as mean (% coefficient of variation; %CV) unless otherwise specified

b Presented as apparent clearance or volume of distribution

c Following administration of radiolabeled omadacycline

Cmax = maximum plasma concentration, AUC = area under concentration-time curve, IV = intravenous, ND = not determined, Tmax = time to Cmax

Absorption

The exposure to omadacycline is similar between a 300-mg oral dose and a 100-mg intravenous dose of omadacycline in healthy fasted subjects.

Effect of Food

Ingestion of a standard high-fat nondairy meal (855 calories; 59% calories from fat) and standard high-fat meal including dairy (985 calories; 60% calories from fat) 2-hours before administration of a single 300-mg oral dose of omadacycline decreased the rate (Cmax) and extent of absorption (AUC) by 40% and 42%, and 59% and 63%, respectively compared to administration of omadacycline under fasting conditions. The rate and extent of absorption of omadacycline were not substantially decreased when a high-fat nondairy meal (800-1000 calories; 50% calories from fat) was ingested 4 hours pre-dose.

Following ingestion of either a light non-fat (300-350 calories; ≤5% calories from fat), or a standard low-fat (800-1000 calories; 30% calories from fat), or a standard high fat (800-1000 calories; 50% calories from fat) meal 2 hours post-dose, the AUC and Cmax were not substantially altered, as compared to fasting conditions.

Distribution

Plasma protein binding of omadacycline is approximately 20% and is not concentration dependent. The mean (% CV) volume of distribution of omadacycline at steady-state following IV administration of omadacycline in healthy subjects was 190 (27.7) L.

Elimination

Renal clearance of omadacycline following IV administration of omadacycline ranged from 2.4 to 3.3 L/h in healthy subjects.

Metabolism

In vitro studies using human liver microsomes and hepatocytes demonstrated that omadacycline is not metabolized.

Excretion

Following a 100-mg IV dose of omadacycline, 27% of the dose was recovered as unchanged omadacycline in the urine. In healthy male volunteers receiving 300-mg oral [14C] omadacycline, 77.5% to 84.0% of the dose was recovered in the feces, approximately 14.4 % (range 10.8% to 17.4%) in the urine, with 95.5% of the administered radioactive dose recovered after 7 days.

Lung Penetration

The mean omadacycline concentrations over time for alveolar cells (AC), epithelial lining fluid (ELF), and plasma following IV administration of multiple doses of 100-mg of omadacycline to healthy volunteers are shown in Figure 1. The steady-state omadacycline AUC0-24h (302.5 hr*mcg/mL) in AC was 25.8-fold higher than the plasma AUC0-24h, and the AUC0-24h (17.2 hr*mcg/mL) in ELF was 1.5-fold higher than the AUC0-24h in plasma.

Figure 1: Mean (± SD) Concentrations of Omadacycline in Alveolar Cells, Epithelial Lining, and Plasma Following Multiple 100 mg IV Doses of Omadacycline to Healthy Subjects During Bronchoscopy Sampling Times

Specific Populations

No clinically significant differences in the pharmacokinetics of omadacycline were observed based on age, gender, race, weight, renal impairment or end-stage renal disease, and hepatic impairment.

Patients with Renal Impairment

A study was conducted to compare omadacycline pharmacokinetics following 100-mg IV administration in 8 subjects with end-stage renal disease (ESRD) on stable hemodialysis, with and 8 -matched healthy control subjects. In the ESRD subjects, omadacycline was administered on two separate occasions; immediately prior to dialysis and after dialysis, and the AUC, Cmax, and CL of omadacycline were comparable between the renally impaired subjects and the matching healthy subjects. During dialysis, 7.9% of omadacycline was recovered in the dialysate. Renal impairment did not impact omadacycline elimination.

Patients with Hepatic Impairment

A study was conducted to compare omadacycline pharmacokinetics following intravenous and oral dosing to 5 subjects with mild hepatic impairment (Child-Pugh Class A), 6 subjects with moderate hepatic impairment (Child-Pugh Class B), and 6 subjects with severe hepatic impairment (Child-Pugh Class C) as compared to 12 matched healthy control subjects. The AUC and Cmax of omadacycline were comparable between the hepatically impaired subjects and the matching healthy subjects, and similar clearance was observed across all cohorts. Hepatic impairment did not impact omadacycline elimination.

Drug Interaction Studies

Clinical Studies

Administration of oral verapamil (P-gp inhibitor) two hours prior to a single 300 mg oral dose of omadacycline increased omadacycline AUC by approximately 25% and Cmax by approximately 9%.

In-vitro Studies

In-vitro studies in human liver microsomes indicate that omadacycline does not inhibit nor induce metabolism mediated by CYP 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5, or UGT1A1. Therefore, omadacycline is not expected to alter the pharmacokinetics of drugs metabolized by the above stated human hepatic enzymes.

Omadacycline is not an inhibitor of P-gp and organic anion transporting polypeptide (OATP) 1B1 and OATP1B3. Omadacycline is a substrate of P- gp (see Clinical Studies above). Omadacycline is not a substrate or inhibitor of the major organic anion transporters (OAT-1 and 3), breast cancer resistance protein (BCRP), or multidrug resistance-associated protein 2 (MRP2). Omadacycline was not an OATP1B1 or OATP1B3 substrate at supra-therapeutic concentrations (5-13 fold higher than clinically relevant concentrations).

13. HOW SUPPLIED/STORAGE AND HANDLING

How Supplied:

NUZYRA for Injection

NUZYRA for Injection is supplied as a sterile lyophilized powder in a single-dose colorless glass vial, with each vial containing 100 mg of NUZYRA (equivalent to 131 mg omadacycline tosylate).

They are supplied as follows: 100-mg single-dose vial (NDC 71715-001-02), packaged in cartons of 10.

NUZYRA Tablets

NUZYRA Tablets contains 150 mg of omadacycline (equivalent to 196 mg omadacycline tosylate) in yellow, diamond-shaped, film-coated tablets debossed with OMC on one side and 150 on the other side.

They are supplied as follows: Bottles of 30 tablets with child-resistant caps (NDC 71715-002-12).

Storage and Handling:

NUZYRA for Injection and NUZYRA Tablets should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature] [see Dosage and Administration (3.5)]. Do not freeze.

Rx only

Rev 10/18