Xerava

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions : Life-threatening hypersensitivity (anaphylactic) reactions have been reported with tetracycline antibacterial drugs, including XERAVA. Avoid use in patients with known hypersensitivity to tetracyclines. ( 5.1 ) Tooth Discoloration and Enamel Hypoplasia : The use of XERAVA 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. ( 5.2 , 8.1 , 8.4 ) Inhibition of Bone Growth : The use of XERAVA 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. ( 5.3 , 8.1 , 8.4 ) Clostridioides difficile -Associated Diarrhea: Evaluate if diarrhea occurs. ( 5.4 ) 5.1 Hypersensitivity Reactions Life-threatening hypersensitivity (anaphylactic) reactions have been reported with XERAVA [see Adverse Reactions ( 6.1 )] . XERAVA is structurally similar to other tetracycline-class antibacterial drugs and should be avoided in patients with known hypersensitivity to tetracycline- class antibacterial drugs. Discontinue XERAVA if an allergic reaction occurs. 5.2 Tooth Discoloration and Enamel Hypoplasia The use of XERAVA during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-grey-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 XERAVA 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 XERAVA 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 XERAVA is used during the second or third trimester of pregnancy [see Use in Specific Populations ( 8.1 , 8.4 )] . 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 Adverse Reactions XERAVA is structurally similar to tetracycline-class 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 XERAVA. Discontinue XERAVA if any of these adverse reactions is suspected. 5.6 Potential for Microbial Overgrowth XERAVA use may result in overgrowth of non-susceptible organisms, including fungi. If such infections occur, discontinue XERAVA and institute appropriate therapy. 5.7 Development of Drug-Resistant Bacteria Prescribing XERAVA 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 ( 1.2 )].

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described in greater detail in the Warnings and Precautions section: Hypersensitivity Reactions [Warning and Precautions ( 5.1 )] Tooth Discoloration [ Warning and Precautions ( 5.2 )] Inhibition of Bone Growth [Warning and Precautions ( 5.3 )] Clostridioides difficile -Associated Diarrhea [Warning and Precautions ( 5.4 )] Tetracycline Class Adverse Reactions [Warning and Precautions ( 5.5 )] Most common adverse reactions (incidence ≥ 3%) are infusion site reactions, nausea, and vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Tetraphase Pharmaceuticals, Inc., at 1-800-651-3861 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. XERAVA was evaluated in 3 active-controlled clinical trials (Trial 1, Trial 2, and Trial 3) in adults with cIAI. These trials included two Phase 3 trials (Trial 1 and Trial 2) and one Phase 2 trial (Trial 3, NCT01265784). The Phase 3 trials included 520 patients treated with XERAVA and 517 patients treated with comparator antibacterial drugs (ertapenem or meropenem). The median age of patients treated with XERAVA was 56 years, ranging between 18 and 93 years old; 30% were age 65 years and older. Patients treated with XERAVA were predominantly male (57%) and Caucasian (98%). The XERAVA-treated population included 31% obese patients (BMI ≥ 30 kg/m2) and 8% with baseline moderate to severe renal impairment (calculated creatinine clearance 15 to less than 60 mL/min). Among the trials, 66 (13%) of patients had baseline moderate hepatic impairment (Child Pugh B); patients with severe hepatic impairment (Child Pugh C) were excluded from the trials. Adverse Reactions Leading to Discontinuation Treatment discontinuation due to an adverse reaction occurred in 2% (11/520) of patients receiving XERAVA and 2% (11/517) of patients receiving the comparator. The most commonly reported adverse reactions leading to discontinuation of XERAVA were related to gastrointestinal disorders. Most Common Adverse Reactions Adverse reactions occurring at 3% or greater in patients receiving XERAVA were infusion site reactions, nausea, and vomiting. Table 1 lists adverse reactions occurring in ≥ 1% of patients receiving XERAVA and with incidences greater than the comparator in the Phase 3 cIAI clinical trials. A similar adverse reaction profile was observed in the Phase 2 cIAI clinical trial (Trial 3). Table 1: Selected Adverse Reactions Reported in ≥ 1% of Patients Receiving XERAVA in the Phase 3 cIAI Trials (Trial 1 and Trial 2) Adverse Reactions XERAVA XERAVA dose equals 1 mg/kg every 12 hours IV. N=520 n (%) Comparators Comparators include ertapenem 1 g every 24 hours IV and meropenem 1 g every 8 hours IV. N=517 n (%) Abbreviations: IV=intravenous Infusion site reactions Infusion site reactions include: catheter/vessel puncture site pain, infusion site extravasation, infusion site hypoaesthesia, infusion/injection site phlebitis, infusion site thrombosis, injection site/vessel puncture site erythema, phlebitis, phlebitis superficial, thrombophlebitis, and vessel puncture site swelling. 40 (7.7) 10 (1.9) Nausea 34 (6.5) 3 (0.6) Vomiting 19 (3.7) 13 (2.5) Diarrhea 12 (2.3) 8 (1.5) Hypotension 7 (1.3) 2 (0.4) Wound dehiscence 7 (1.3) 1 (0.2) Other Adverse Reactions of XERAVA The following selected adverse reactions were reported in XERAVA-treated patients at a rate of less than 1% in the Phase 3 trials: Cardiac disorders: palpitations Gastrointestinal System: acute pancreatitis, pancreatic necrosis General Disorders and Administrative Site Conditions: chest pain Immune system disorders: hypersensitivity Laboratory Investigations: increased amylase, increased lipase, increased alanine aminotransferase, prolonged activated partial thromboplastin time, decreased renal clearance of creatinine, increased gamma-glutamyltransferase, decreased white blood cell count, neutropenia Metabolism and nutrition disorders: hypocalcemia Nervous System: dizziness, dysgeusia Psychiatric disorders: anxiety, insomnia, depression Respiratory, Thoracic, and Mediastinal System: pleural effusion, dyspnea Skin and subcutaneous tissue disorders: rash, hyperhidrosis

<table cellpadding="3.6pt" width="75%"><caption>Table 1: Selected Adverse Reactions Reported in &#x2265; 1% of Patients Receiving XERAVA in the Phase 3 cIAI Trials (Trial 1 and Trial 2)</caption><col width="50%" align="left" valign="top"/><col width="25%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><thead><tr><th valign="bottom" styleCode="Lrule Rrule"> Adverse Reactions </th><th styleCode="Rrule"> XERAVA<footnote>XERAVA dose equals 1 mg/kg every 12 hours IV.</footnote> N=520 n (%) </th><th styleCode="Rrule"> Comparators<footnote>Comparators include ertapenem 1 g every 24 hours IV and meropenem 1 g every 8 hours IV.</footnote> N=517 n (%) </th></tr></thead><tfoot><tr><td align="left" colspan="3" valign="top">Abbreviations: IV=intravenous</td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Infusion site reactions<footnote>Infusion site reactions include: catheter/vessel puncture site pain, infusion site extravasation, infusion site hypoaesthesia, infusion/injection site phlebitis, infusion site thrombosis, injection site/vessel puncture site erythema, phlebitis, phlebitis superficial, thrombophlebitis, and vessel puncture site swelling.</footnote></td><td styleCode="Rrule"> 40 (7.7) </td><td styleCode="Rrule"> 10 (1.9) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nausea </td><td styleCode="Rrule"> 34 (6.5) </td><td styleCode="Rrule"> 3 (0.6) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Vomiting </td><td styleCode="Rrule"> 19 (3.7) </td><td styleCode="Rrule"> 13 (2.5) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Diarrhea </td><td styleCode="Rrule"> 12 (2.3) </td><td styleCode="Rrule"> 8 (1.5) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hypotension </td><td styleCode="Rrule"> 7 (1.3) </td><td styleCode="Rrule"> 2 (0.4) </td></tr><tr><td styleCode="Lrule Rrule"> Wound dehiscence </td><td styleCode="Rrule"> 7 (1.3) </td><td styleCode="Rrule"> 1 (0.2) </td></tr></tbody></table>