NUZYRA

5 WARNINGS AND PRECAUTIONS Tooth Discoloration and Enamel Hypoplasia : The use of NUZYRA during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown) and enamel hypoplasia. ( 5.1 , 8.1 , 8.4 ) 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. ( 5.2 , 8.1 , 8.4 ) Clostridioides difficile -Associated Diarrhea : Evaluate if diarrhea occurs. ( 5.4 ) 5.1 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) ]. 5.2 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) ] . 5.3 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. 5.4 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. 5.5 Tetracycline Class Effects NUZYRA is structurally similar to tetracycline class of antibacterial drugs and may have similar adverse reactions. Adverse reactions including photosensitivity, fixed drug eruption, 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. 5.6 Development of Drug-Resistant Bacteria Prescribing NUZYRA in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication 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: Tooth Development and Enamel Hypoplasia [see Warnings and Precautions (5.1) ] Inhibition of Bone Growth [see Warnings and Precautions (5.2) ] Hypersensitivity Reactions [see Warnings and Precautions (5.3) ] Tetracycline Class Effects [see Warnings and Precautions ( 5.5 )] ABSSSI: The most common adverse reactions (incidence ≥2%) are nausea, vomiting, infusion site reactions, alanine aminotransferase increased, aspartate aminotransferase increased, headache and diarrhea. CABP : The most common adverse reactions (incidence ≥2%) are alanine aminotransferase increased, headache, hypertension, and aspartate aminotransferase increased. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Paratek Pharmaceuticals, Inc. at 1-833-727-2835 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 pivotal clinical trials (Trial 1, Trial 2 and Trial 3) and one Phase 3 postmarketing clinical trial (Trial 4). These trials included one pivotal Phase 3 trial in CABP patients (Trial 1), one Phase 3 postmarketing trial in CABP patients (Trial 4), and two pivotal Phase 3 trials in ABSSSI patients (Trial 2 and Trial 3). Across all Phase 3 trials, a total of 1409 patients were treated with NUZYRA. In Trials 2 and 3, 691 patients with ABSSSI received NUZYRA, of which 368 patients were treated with only oral NUZYRA. In Trials 1 and 4, 718 patients with CABP were treated with 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/m 2 . 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. Trial 4 was a Phase 3 CABP trial that enrolled 670 adult patients, 336 randomized to NUZYRA (all 336 received at least one dose of NUZYRA) and 334 randomized to moxifloxacin (332 received at least one dose of moxifloxacin and 2 patients did not receive the study drug). The mean age of patients treated with NUZYRA was 63.3 years (range 23 to 96 years) and 47.6% were greater than or equal to 65 years of age. Overall, patients treated with NUZYRA were predominantly male (53.0%), white (99.7%), and had a mean body mass index (BMI) of 27.0 kg/m 2 . Approximately 54% 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 10 days with up to 14 days allowed for patients with positive blood cultures at the Screening visit. Mean duration of IV treatment was 6.6 days and mean total duration of treatment was 9.0 days in both treatment arms. 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. There were eight deaths (2%) in 382 patients treated with NUZYRA as compared to four deaths (1%) in 388 patients treated with moxifloxacin. 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. In Trial 4, a total of 17/336 (5.1%) patients treated with NUZYRA and 15/332 (4.5%) patients treated with moxifloxacin experienced serious adverse reactions. There were six deaths (1.8%) in each treatment group (6/336 in the NUZYRA group, and 6/332 in the moxifloxacin group). Discontinuation of treatment due to any adverse reactions occurred in 9/336 (2.7%) patients treated with NUZYRA and 9/332 (2.7%) patients treated with moxifloxacin. Most Common Adverse Reactions Table 4 lists the most common adverse reactions occurring in ≥2% of CABP patients receiving NUZYRA in Trial 1 and Trial 4. Table 4: Adverse Reactions Occurring in ≥2% of CABP Patients Receiving NUZYRA in Pooled Trials 1 and Trial 4 Adverse Reaction NUZYRA (N = 718) Moxifloxacin (N = 720) Alanine aminotransferase increased 2.8 2.6 Headache 2.8 2.8 Hypertension 2.2 1.7 Aspartate aminotransferase increased 2.1 1.9 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 28.1 kg/m 2 . 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/m 2 . 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 ABSSSI 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 ABSSSI Patients Receiving NUZYRA in Pooled Trials 2 and 3 Adverse Reaction NUZYRA (N = 691) Linezolid (N = 689) Nausea 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 21.9 8.7 Vomiting 11.4 3.9 Infusion site reactions Infusion site extravasation, pain, erythema, swelling, inflammation, irritation, peripheral swelling and skin induration. 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 ABSSSI and CABP Patients Receiving NUZYRA in Trials 1, 2, 3, and 4 The following selected adverse reactions were reported in NUZYRA-treated patients at a rate of less than 2% in Trials 1, 2, 3, and 4. Cardiovascular System Disorders: tachycardia, atrial fibrillation Blood and Lymphatic System Disorders: anemia, thrombocytosis Ear and Labyrinth Disorders: vertigo Gastrointestinal Disorders: constipation, abdominal pain, dyspepsia General Disorders and Administration Site Conditions: fatigue Immune System Disorders: hypersensitivity Infections and Infestations: oral candidiasis, vulvovaginal mycotic infection Investigations: gamma glutamyl transferase increased, creatinine phosphokinase increased, bilirubin increased, lipase increased, alkaline phosphatase increased Nervous System Disorders: dysgeusia, lethargy Psychiatric Disorders: Insomnia Respiratory, Thoracic, and Mediastinal disorders: oropharyngeal pain Skin and Subcutaneous Tissue Disorders: pruritus, erythema, hyperhidrosis, urticaria 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of NUZYRA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and Subcutaneous Tissue Disorders: rash

<table><caption>Table 4: Adverse Reactions Occurring in &#x2265;2% of CABP Patients Receiving NUZYRA in Pooled Trials 1 and Trial 4</caption><col/><col/><col/><thead><tr><th styleCode=" Botrule Toprule Lrule Rrule" valign="top">Adverse Reaction</th><th align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top">NUZYRA (N = 718) </th><th align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top">Moxifloxacin (N = 720) </th></tr></thead><tbody><tr><td styleCode=" Botrule Toprule Lrule Rrule" valign="top">Alanine aminotransferase increased</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top">2.8</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top">2.6</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule" valign="top">Headache</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top">2.8</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top">2.8</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule" valign="top">Hypertension</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top">2.2</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top">1.7</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule" valign="top">Aspartate aminotransferase increased</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top">2.1</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top">1.9</td></tr></tbody></table>

<table><caption>Table 5: Adverse Reactions Occurring in &#x2265;2% of ABSSSI Patients Receiving NUZYRA in Pooled Trials 2 and 3</caption><col/><col/><col/><thead><tr><th styleCode=" Botrule Toprule Lrule Rrule" valign="top">Adverse Reaction</th><th align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top">NUZYRA (N = 691) </th><th align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top">Linezolid (N = 689) </th></tr></thead><tbody><tr><td styleCode=" Botrule Toprule Lrule Rrule" valign="top">Nausea <footnote ID="FOOT_26031">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</footnote></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top">21.9</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top">8.7</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule" valign="top">Vomiting</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top">11.4</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top">3.9</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule" valign="top">Infusion site reactions <footnote ID="FOOT_26032">Infusion site extravasation, pain, erythema, swelling, inflammation, irritation, peripheral swelling and skin induration.</footnote></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top">5.2</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top">3.6</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule" valign="top">Alanine aminotransferase increased</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top">4.1</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top">3.6</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule" valign="top">Aspartate aminotransferase increased</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top">3.6</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top">3.5</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule" valign="top">Headache</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top">3.3</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top">3.0</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule" valign="top">Diarrhea</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top">3.2</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top">2.9</td></tr></tbody></table>