NUZYRA (Page 2 of 7)

3 DOSAGE FORMS AND STRENGTHS

3.1 NUZYRA for Injection

Each single-dose vial contains 100 mg omadacycline (equivalent to 131 mg omadacycline tosylate) which must be reconstituted and further diluted prior to intravenous infusion. The lyophilized powder is a yellow to dark orange cake.

3.2 NUZYRA Tablets

Each tablet 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.

4 CONTRAINDICATIONS

NUZYRA 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 NUZYRA 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 NUZYRA 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 NUZYRA 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 NUZYRA 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 NUZYRA 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 NUZYRA [see Adverse Reactions (6.1)]. Life-threatening hypersensitivity (anaphylactic) reactions have been reported with other tetracycline-class antibacterial drugs. NUZYRA 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 NUZYRA if an allergic reaction occurs.

5.5 Clostridioides difficile- Associated Diarrhea

Clostridioides 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

NUZYRA 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 NUZYRA. Discontinue NUZYRA if any of these adverse reactions are suspected.

5.7 Development of Drug-Resistant Bacteria

Prescribing NUZYRA 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 (1.3)].

6 ADVERSE REACTIONS

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

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 NUZYRA

NUZYRA 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 NUZYRA (382 patients in Trial 1 and 691 in Trials 2 and 3 of which 368 patients were treated with only oral NUZYRA.

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 NUZYRA (382 received at least one dose of NUZYRA 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 NUZYRA was 61 years (range 19 to 97 years) and 42% were greater than or equal to 65 years of age. Overall, patients treated with NUZYRA were predominantly male (53.7%), white (92.4%), and had a mean body mass index (BMI) of 27.3 kg/m2. Approximately 47% of NUZYRA treated patients had CrCl <90 ml/min. Patients were administered an IV to oral switch dosage regimen of NUZYRA. 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 NUZYRA 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 NUZYRA 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 NUZYRA 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 NUZYRA in Trial 1.

Table 4: Adverse Reactions Occurring in ≥2% of Patients Receiving NUZYRA in Trial 1
Adverse Reaction NUZYRA(N = 382) Moxifloxacin(N = 388)
Alanine aminotransferase increased 3.7 4.6
Hypertension 3.4 2.8
Gamma-glutamyl transferase increased 2.6 2.1
Insomnia 2.6 2.1
Vomiting 2.6 1.5
Constipation 2.4 1.5
Nausea 2.4 5.4
Aspartate aminotransferase increased 2.1 3.6
Headache 2.1 1.3

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

In Trial 2 (IV to oral switch trial), the mean age of patients treated with NUZYRA was 47 years (range 19 to 88). Overall, patients treated with NUZYRA 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 NUZYRA 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 NUZYRA 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 NUZYRA 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 NUZYRA and 13/689 (1.9%) of patients treated with comparator. Discontinuation of treatment due to adverse events occurred in 12 (1.7%) NUZYRA treated patients, and 10 (1.5%) comparator treated patients. There was 1 death (0.1%) reported in NUZYRA 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 NUZYRA in Trials 2 and 3.

Table 5: Adverse Reactions Occurring in ≥2% of Patients Receiving NUZYRA in Pooled Trials 2 and 3
Adverse Reaction NUZYRA(N = 691) Linezolid(N = 689)
*
In Trial 2, which included IV to oral dosing of NUZYRA, 40 (12%) patients experienced nausea and 17 (5%) patients experienced vomiting in NUZYRA 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 NUZYRA group discontinued treatment due to nausea and vomiting. In Trial 3, which included the oral loading dose of NUZYRA, 111 (30%) patients experienced nausea and 62 (17%) patients experienced vomiting in NUZYRA 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 NUZYRA group discontinued treatment due to nausea and vomiting
Infusion site extravasation, pain, erythema, swelling, inflammation, irritation, peripheral swelling and skin induration.
Nausea * 21.9 8.7
Vomiting 11.4 3.9
Infusion site reactions 5.2 3.6
Alanine aminotransferase increased 4.1 3.6
Aspartate aminotransferase increased 3.6 3.5
Headache 3.3 3.0
Diarrhea 3.2 2.9

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

The following selected adverse reactions were reported in NUZYRA-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

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