CLINICAL TRIAL PROTOCOL

A Phase 3, Randomized, Double-Blind, Double-Dummy, Multicenter, Prospective Study to Assess the Efficacy and Safety of Eravacycline Compared with Ertapenem in Complicated Intra-abdominal Infections

Protocol No.: TP-434-008

Sponsor: Tetraphase Pharmaceuticals, Inc. 480 Arsenal Street, Suite 110 Watertown, MA 02472 USA Phone: +1-617-715-3600 Fax: +1-617-926-3557

EudraCT No.: 2013-001913-34

ClinicalTrials.gov No.: NCT01844856

Version 3.0: 31 October 2013 This study will be conducted according to the protocol and in compliance with Good Clinical Practice (GCP), the Declaration of Helsinki, and applicable regulatory requirements. CONFIDENTIAL The information in this study protocol is strictly confidential and is available for review to Investigators, study site personnel, the Institutional Review Board (IRB)/Independent Ethics Committee (IEC), and the Regulatory Authorities. It will not be disclosed to third parties without written authorization from Tetraphase Pharmaceuticals, Inc. (the Sponsor), except to obtain informed consent from persons participating in the trial. Once the protocol is signed, its terms are binding for all parties.

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INVESTIGATOR AGREEMENT I have read this protocol and agree that it contains all necessary details for carrying out this study. I will conduct the study as outlined herein and will complete the study within the time designated. This trial will be conducted according to all stipulations of the protocol, including all statements regarding confidentiality, and according to local legal and regulatory requirements and applicable United States federal regulations and International Conference on Harmonization (ICH) guidelines.

I will provide copies of the protocol and all pertinent information to all individuals responsible to me who assist in the conduct of this study. I will discuss this material with them to ensure they are fully informed regarding the drug and the conduct of the study.

I will use only the informed consent form approved by the Sponsor or its representative and will fulfill all responsibilities for submitting pertinent information to the Institutional Review Board/Independent Ethics Committee (IRB/IEC) responsible for this study.

I agree that the Sponsor or its representatives shall have access to any source documents from which case report form information may have been generated. I agree that regulatory authorities (FDA, EMA, and other local and country-related agencies) can audit and review source documents.

I further agree not to originate or use the name of Tetraphase Pharmaceuticals, Inc.or any of its employees, in any publicity, news release, or other public announcement, written or oral, whether to the public, press, or otherwise, relating to his protocol, to any amendment hereto, or to the performance hereunder, without the prior written consent of Tetraphase Pharmaceuticals, Inc.

______Investigator’s Signature Date

______Name of Investigator (Typed or Printed)

______Institution Name

______Institution Address

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2. TABULATED PROTOCOL SUMMARY Name of Sponsor/Company: Tetraphase Pharmaceuticals, Inc.

Name of Finished Products: Eravacycline for intravenous administration; and Invanz® (comparator)

Name of Active Ingredients: Eravacycline (TP-434) and ertapenem (comparator)

Title of Study: A Phase 3, Randomized, Double-Blind, Double-Dummy, Multicenter, Prospective Study to Assess the Efficacy and Safety of Eravacycline Compared with Ertapenem in Complicated Intra-abdominal Infections Indication: Complicated Intra-abdominal Infections (cIAI)

Anticipated Study Period: 3Q 2013-4Q 2014

Objectives: Primary Objective: ƒ Compare the clinical response at the test-of-cure (TOC) visit in the microbiological intent-to-treat (micro-ITT) population for subjects in the 2 treatment arms NOTE: For the EMA, the primary analysis populations will be the all-treated (MITT) and the clinically evaluable (CE) populations Secondary Objectives: ƒ Compare the clinical response for subjects in the 2 treatment arms at the end-of-treatment (EOT), TOC, and follow-up (FU) visits in the following populations: - Intent-to-treat (ITT) population - All-treated (MITT) - Clinically evaluable (CE) population - Micro-ITT population (for EOT and FU) - Microbiologically evaluable (ME) population ƒ Compare the microbiologic response in the treatment arms at the EOT and TOC visits in the following populations: - Micro-ITT population - ME population ƒ Assess the safety and tolerability of eravacycline administration in the safety population ƒ Explore pharmacokinetic (PK) parameters after eravacycline infusion including Cmax, Tmax, AUC0-12 Methodology: This is a phase 3, randomized, double-blind, double-dummy, multicenter, prospective study to assess the efficacy, safety and PK of eravacycline (1.0 mg/kg every 12 hours [q12h]) compared with ertapenem (1 g q24h) in the treatment of cIAIs. Once an informed consent is obtained and study eligibility is established, subjects will be enrolled and randomized to eravacycline (1.0 mg/kg up to a maximum of 150 mg q12h) or ertapenem (1 g q24h) treatment arms in a 1:1 ratio. Randomization will be stratified based on primary site of infection (complicated appendicitis versus all other diagnoses). An enrollment cap of approximately 30% complicated appendicitis is planned. Specified study personnel will remain blinded to the identity of intravenous (IV) study drug until the database has been locked. Study drug will be administered in 24-h dosing cycles according to the schedule below: Study Drug Infusion Scheme of a 24-h Dosing Cycle Initial Dose Follow-up Dose Study Drug Bag 1 Bag 2 Bag N/A 60 min infusion 30 min infusion 60 min infusion Eravacycline, 1.0 mg/kg q12h Eravacycline Placebo Eravacycline Ertapenem, 1 g q24h Placebo Ertapenem Placebo

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The amount of eravacycline administered during any given 24-h dosing cycle is not to exceed 300 mg (ie, each infusion must be ”PJRIHUDYDF\FOLQH  Eravaycline concentration may be decreased (as long as the total infusion volume is ” 500 mL) and/or infusion time may be increased (to 120 minutes per IV bag) to manage infusion site reactions. See Section 15.2.2. The 12-h interval between doses can be reduced by up to 2 hours in each of the 3 initial 24-h dosing cycles. The investigator should collect appropriate specimens for culture by aspiration and/or tissue samples at the time of the initial procedure and inoculate into appropriate media for aerobes and anaerobes immediately. These specimens will be cultured and quantified in the local laboratory or a reference regional laboratory. The isolate(s) will be sent to a central microbiology laboratory for validation of identification and susceptibility testing. In addition, blood cultures will be collected at screening, prior to first dose. Upon knowledge of a positive culture for a pathogen, blood cultures should be repeated until sterile (ie, both sets of cultures from two separate venipuncture sites are negative for pathogens) through the EOT visit. If baseline cultures are negative, follow up cultures should be obtained only if clinically indicated (eg, worsening of signs and symptoms, relapse, or new infection). Ertapenem will be used in accordance with its most recent prescribing information. Study Design Overview: STUDY DRUG END-OF- TEST-OF-CURE FOLLOW-UP SCREENING ENROLLMENT TREATMENT THERAPY (EOT) (TOC) (FU) Within 48-h of Day 1 (Dose Cycle 1) Within 24-h of Day 25-31 Day 38-50 First Dose through EOT Last Dose Establish diagnosis Use IWRS* to Infuse study drug, Review of subjects Return to study Return to study of complicated randomize to either: with Medical center for center for intra- study drug Monitor for assessment of assessment of abdominal therapies longer microbiological microbiological and x Eravacycline IV infections (cIAI) than seven 24-h and clinical clinical response 1.0 mg/kg (up to a dosing cycles. response and safety and safety maximum of 150 Verify eligibility mg) q12h for enrollment EOT assessments OR should be performed at x Ertapenem IV premature 1 g q24h withdrawal or Expected 4 (min) to treatment failure 14 (max) study and within 24-h of drug treatment 24-h last dose. dosing cycles. *IWRS= Interactive Web-based Response System Number of Subjects: Approximately 536 subjects will be randomized to receive study drug. Investigative sites will be recruited in approximately 100 centers worldwide. Criteria for Study Entry: Inclusion Criteria: 1. Male or female subject hospitalized for cIAI with one of the following diagnoses: a. Intra-abdominal abscess: one or more abscesses surrounding diseased or perforated viscera b. Gastric or intestinal perforation associated with diffuse peritonitis c. Peritonitis due to perforated viscus, or other focus of infection (but not spontaneous bacterial peritonitis associated with cirrhosis and chronic ascites) d. Appendicitis with perforation, peritonitis or abscess e. Cholecystitis with perforation or abscess f. Intra-abdominal abscess (single or multiple), including hepatic and splenic abscesses g. Peritonitis (local or diffuse) Note: infections limited to the hollow viscus, such as simple cholecystitis and simple appendicitis, are not eligble. Ischemic bowel disease without perforation is not eligible. Acute suppurative cholangitis and acute necrotizing pancreatitis are not eligible.

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2. At least 18 years of age (and not over 65 years of age for subjects in India) 3. Evidence of a systemic inflammatory response with at least one of the following: a. Fever (oral, rectal, tympanic or by temporal artery WHPSHUDWXUH ! Û)  Û&  RU K\SRWKHUPLD (temperature ” Û)/ Û& b. Elevated WBC (> Upper Limit of Normal (ULN) laboratory range); or proportion of band forms of the WBC differential beyond the ULN laboratory range c. Increased pulse (HR > 90 beats per minute) d. Increased respiratory rate (> 20 breaths per minute) 4. Abdominal pain or flank pain (with or without rebound tenderness), or pain caused by cIAI that is referred to another anatomic area such as back or hip, or localized or diffuse abdominal wall rigidity, or mass, or ileus 5. Able to provide informed consent 6. If male: must agree to use an effective barrier method of contraception during the study and for 30 days following the last dose if sexually active with a female of childbearing potential 7. If female: a. Not pregnant or nursing b. If of childbearing potential, will commit to either: i. Use at least two medically accepted, effective methods of birth control (eg, condom, oral contraceptive, indwelling intrauterine device, hormonal implant /patch, injections, approved cervical ring) during study drug dosing and for 30 days following last study drug dose ii. Sexual abstinence And either 8A. Meets All Inclusion Criteria for Pre-operative Enrollment: ƒ Has a sonogram or radiographic imaging result congruent with the diagnosis of cIAI, AND ƒ Acute surgical or percutaneous intervention (open laparotomy, laparoscopic surgery, or percutaneous drainage of an abscess) is foreseen within 48-h

8B. Meets All Inclusion Criteria for Intra-operative/Post-operative Enrollment: ƒ Visual confirmation of cIAI (presence of pus within the abdominal cavity), AND ƒ Surgical intervention includes open laparotomy, laparoscopic surgery, or percutaneous draining of an abscess, AND ƒ Intervention is adequate [ie, a procedure in which all communications between the gastrointestinal (GI) tract and the peritoneal cavity are closed, no necrotic intestine is left, and all infected collections are drained at the procedure]

Exclusion Criteria: Subjects must NOT meet any of the following exclusion criteria: 1. Considered unlikely to survive the 6-8 week study period ƒ Any rapidly-progressing disease or immediately life-threatening illness, including acute hepatic failure, respiratory failure and septic shock ƒ Requirement for vasopressors (prior to enrollment) at therapeutic dosages (ie, dopamine > 5 μg/kg/min, any dose of norepinephrine, epinephrine, or phenylephrine) to maintain a systolic blood pressure t 90 mm Hg or a mean arterial pressure t 70 mm Hg following adequate fluid resuscitation 2. Renal failure as defined as: a. Threefold increase of serum creatinine to a known previous value, OR b. Decrease in estimated glomerular filtration rate to < 75% of a known previous value, OR c. Urine output of < 0.3 mL/kg/h for > 24-h, OR d. Anuria for > 12-h, OR e. Serum creatinine of > 4 mg/dL (353.6 μmol/L) with an acute rise of 0.5 mg/dL (42.2 μmol/L) compared with a previous value, OR f. Creatinine clearance of < 50 mL/min as estimated by the Cockcroft-Gault equation, OR [݈݁ܽ݉݁ܨ ݂݅ ݋݀ݕ ܹ݄݁݅݃ݐ [݇݃] × [0.85ܤ × ([ݏݎݕ] ݁݃ܣെ 140) ݁ܥ [݉ܮ/݉݅݊]= [ܮ݀ ݐ݅݊݅݊݁ [݉݃Τܽ݁ݎܥ ݑ݉ݎ݁ܵ × ஼௥ 72 g. Requires peritoneal dialysis, hemodialysis, or hemofiltration

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3. Presence or possible signs of significant hepatic disease: a. Alanine aminotransferase or aspartate aminotransferase > 3 x ULN; > 5 x ULN for patients with hepatic abscess, OR b. Total bilirubin > 3 x ULN, unless isolated hyperbilirubinemia is directly related to the acute process, OR c. Alkaline phosphatase > 3 x ULN, OR d. Subjects with diagnosis of hepatic failure 4. Immunocompromised condition, including known HIV positivity (requiring anti-retroviral therapy or with CD4 count < 300), AIDS, organ (bone marrow) transplant recipients, and hematological malignancy. Immunosuppressive therapy, including use of high-dose corticosteroids (eg, > 40 mg prednisone or equivalent per day for greater than 2 weeks) 5. History of moderate or severe hypersensitivity reactions to tetracyclines, carbapenems, ȕ-lactam antibiotics, or to any of the excipients contained in the study drug formulations 6. Participation in any investigational drug or device study within 30 days prior to study entry 7. Known or suspected current central nervous system (CNS) disorder that may predispose to seizures or lower seizure threshold (eg, severe cerebral arteriosclerosis, epilepsy) 8. Previously received eravacycline in a clinical trial 9. Antibiotic-related exclusions: a. Receipt of effective antibacterial drug therapy for cIAI for a continuous duration of > 24-h during the 72-h preceding enrollment [However, subjects with documented cIAI (ie, known baseline pathogen) who have received at least 72-h of antibiotic therapy and are considered treatment failures may be enrolled. Treatment failure is defined as persistent fever and/or clinical symptoms; or the development of a new intra- abdominal abscess after • 72-h of antibiotic therapy], OR b. Receipt of ertapenem or any other carbapenem, or tigecycline for the current infection, OR c. Need for concomitant systemic antimicrobial agents other than study drug 10. Refusal of mechanical ventilation, dialysis or hemofiltration, cardioversion or any other resuscitative measures and drug/fluid therapy at time of consent 11. Known or suspected inflammatory bowel disease or associated visceral abscess 12. The anticipated need for systemic antibiotics for a duration of more than 14 days 13. Systemic malignancy that required chemotherapy, immunotherapy, radiation therapy, or antineoplastic therapy within the previous 3 months or that is anticipated to begin prior to the TOC visit 14. Known at study entry to have cIAI caused by a pathogen(s) resistant to one of the study drugs

Test Product, Dose and Route of Administration: Eravacycline was synthesized under current good manufacturing practices, and the drug product contains 53.0 mg (TP-434 free base equivalents) of lyophilized powder in a 10 mL vial. Eravacycline will be reconstituted with 5 mL of sterile water and further diluted with sterile 0.5x normal saline, to generate 0.3 mg/mL eravacycline solutions for 1.0 mg/kg up to a maximum of 150 mg q12h IV infusions. Please refer to Section 15.2.1 and the Pharmacy Manual for additional information on reconstitution. Reference Therapy, Dose and Route of Administration: Ertapenem 1 g administered by IV q24h. Ertapenem infusion solutions will be prepared according to the full prescribing information of Invanz® (comparator). Duration of Treatment: The expected minimum treatment duration is four 24-h dosing cycles unless Clinical Failure or Clinical Cure occurs earlier. Maximum treatment duration is fourteen 24-h dosing cycles. Subjects will remain on study drug treatment until symptoms of cIAI have resolved. If study drug is needed for longer than seven 24-h dosing cycles, cases will be reviewed by the Medical Monitor. The TOC visit will be 25-31 days after the initial dose of study drug. The follow-up visit will be conducted 38-50 days after the initial dose of study drug. Pharmacokinetics:

Cmax, Tmax,and AUC0-12 will be determined. Statistical Methods and Criteria for Evaluation:

Sample Size Estimate: This study is designed to demonstrate non-inferiority of 1.0 mg/kg (up to a maximum of 150 mg) q12h eravacycline to

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ertapenem, and a 10% non-inferiority margin will be used to determine success. A non-inferiority trial with a one-sided alpha of 0.025, 80% power, a non-inferiority margin (delta) of 10%, and projected response rates of 85% for both arms would need 201 subjects per arm in the micro-ITT population. A sample size of approximately 536 randomized subjects should provide sufficient numbers for this study, assuming 75% of enrolled subjects will meet the requirements for inclusion in the micro-ITT population. NOTE: For the EMA, a 12.5% non-inferiority margin will be used to determine success. In this case, using the same assumptions of response rate (85%) and eligibility (75%) and powering the study at 80%, the two-sided alpha is 0.008. Safety: Safety analyses will be conducted on the safety population. Subjects will be analyzed according to the treatment received. Adverse Events Verbatim descriptions of AEs will be mapped to Preferred Terms and System Organ Classes using MedDRA and tabulated by treatment arm. The number and percentage of subjects who experience treatment-emergent AEs and serious AEs (SAEs) will be presented by reporting levels for System Organ Class and Preferred Term. Tabulations by severity and by relationship to study drug, as reported by the investigators, will also be provided. Deaths and premature discontinuations from study drug due to an AE will be identified. Laboratory Data Hematology, chemistry, and where applicable, urinalysis data will be summarized using shift tables based on the upper and lower limits of the normal range, change from baseline, and the number and percentage of subjects with clinically notable values. Clinically notable values will be specified in the Statistical Analysis Plan. Other Safety Data Physical examination, including resting vital signs and ECG findings will be reported (as warranted) and analyzed as AEs. Efficacy Assessments: Clinical response rates will be determined, along with 95% CIs, for each treatment arm overall and for each of the randomization strata (ie, primary site of infection). The clinical response rate will be determined as the number of subjects with Clinical Cure (ie, complete or significant improvement of signs or symptoms such that no further systemic antibiotic treatment is required) at the respective visit divided by the number of subjects in the analysis population (ie, overall or by randomization strata). A 95% CI around the difference in the eravacycline and ertapenem response rates will be used to determine if eravacycline is non-inferior to ertapenem. Per pathogen and per subject microbiological response rates will be determined, along with 95% CIs, by treatment arm. The per pathogen microbiological response rate will be determined as the number of subjects with a favorable response (ie, eradication or presumptive eradication) at the respective visit divided by the number of subjects in the analysis population with that pathogen at baseline. The per subject microbiological response rate will be determined as the number of subjects with a favorable response (ie, eradication or presumptive eradication) at the respective visit divided by the number of subjects in the analysis population. Microbiology: Bacterial isolates cultured from aerobic and anaerobic cIAI specimens and blood will be evaluated for susceptibility and the emergence of resistance to study drugs and overgrowth of non-susceptible organisms.

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3. SCHEDULE OF ASSESSMENTS The calendar day on which the first study drug infusion of the first 24-h dosing cycle is administered is Day 1. 1 Screening 1 Days 4-14 Day 1 Day 2 Day 3 2 TOC FU Study Procedure Within 48-h (Dose Cycles EOT (Dose Cycle 1) (Dose Cycle 2) (Dose Cycle 3) Day 25-31 Day 38-50 of First Dose 4-14) Informed Consent X Medical History/ Height and Weight X 3 APACHE II score X Physical Exam X X X X 4 Temperature X X X X X X X X 5 Resting Vital Signs X X X X X X X X 6 Abdominal Exam X X X X X X X X 7 Prior/Concomitant Medications X X X X X X X X 8 Hematology/Chemistry X X X X X X2 X X 9 Coagulation/ Urinalysis X X X2 Calculated Creatinine Clearance X 10 Serum Pregnancy Test X X X X 11 2 Blood Cultures X ENROLLMENT X X X X X 12 Intra-abdominal Cultures X X X X X2 X X 13 Extra-abdominal/Wound Cultures X X X X X2 X X 14 Radiologic Examination X X X X X X X X 12-Lead ECG X X Adverse Events X X X X X X X Clinical Response X X X 15 Study Drug Administration X X X X 16 PK Assessments X See footnotes on following page(s).

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1. If Cycle 1 and Screening occur on the same day the resting vital signs, abdominal exam, and safety labs do not need to be repeated. 2. EOT assessments are to be performed at: (i) premature withdrawal, (ii) treatment failure, or (iii) within 24-h of last dose. If EOT occurs on the same day as a Dosing Cycle day, then safety labs and any cultures do not need to be repeated provided samples are taken after the last dose of study drug. 3. Serum bicarbonate may be used in place of arterial blood gases. Please refere to Appendix 1 for instructions on how to calculate APACHE II Score. 4. Record oral, rectal, tympanic, or by temporal artery prior to {Dose 1, Bag 1} and then q8h ± 1-h while hospitalized until EOT. 5. RR, HR, B/P are performed prior to {Dose 1, Bag 1}; after completion of {Dose 1, Bag 1}; daily while hospitalized; and EOT, TOC,and FU. 6. Performed at least once daily until resolution of all signs and symptoms of cIAI. 7. < 24-h of continuous systemic antibacterial therapy for cIAI during the 72-h preceding enrollment is permitted. Documented cIAI treatment failures with a known EDVHOLQHSDWKRJHQDQG•-h of systemic antibiotic therapy may be enrolled. No concomitant systemic antibacterials are permitted after the initial dose of study drug through the FU visit. All other medically necessary concomitant medications are permitted. 8. Performed at Screening; Days 1-4; every three 24-h dosing cycles thereafter while on study drug; and at EOT, TOC, and FU. 9. Urine microscopy for RBC, WBC, crystals, and casts performed at Screening, Day 1, and EOT. 10. If a serum pregnancy test is not available at the investigator site then a urine pregnancy test may be utilized locally. 11. Obtain two sets of aerobic and anaerobic samples (each set from a separate location) at Screening. Upon knowledge of a positive culture for a pathogen, blood cultures should be repeated until sterile (ie, both sets of cultures from two separate venipuncture sites are negative for pathogens) through the EOT visit. If baseline cultures are negative, follow up cultures should be obtained only if clinically indicated (eg, worsening of signs and symptoms, relapse, or new infection). 12. Collected by aspiration and/or tissue sampling from the site of infection at the time of the initial surgical procedure, subsequent surgical re intervention(s) and if there are signs and symptoms of infection (if applicable). For subjects that enter the study as a documented cIAI treatment failure (ie, with a known baseline pathogen), reasonable attempts should be made to provide the baseline isolates to the central laboratory. 13. Obtained as deemed appropriate by the investigator (eg, re-intervention). 14. Required for pre-operative enrollment. Only to be obtained at appropriate intervals thereafter if deemed necessary by the investigator. 15. The expected minimum treatment duration is four 24-h dosing cycles unless Clinical Failure or Clincal Cure occurs earlier. Maximum treatment duration is fourteen 24-h dosing cycles. The 12-h interval between doses can be shortened (but not prolonged) by up to 2-h from the first dose during dosing cycles 1-3 to adapt to a normal hospital schedule. After the 3rd 24-h dosing cycle (ie, after Dose 6 Bag N/A), the permitted administration window is q12h ± 1-h. Contact Medical Monitor for dosing beyond 7 dosing cycles. 16. Please refer to Appendix 3 for schedule of PK assessments.

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TABLE OF CONTENTS

1. SPONSOR SIGNATURE PAGE...... 2 2. TABULATED PROTOCOL SUMMARY ...... 4 3. SCHEDULE OF ASSESSMENTS ...... 9 4. LIST OF ABBREVIATIONS ...... 15 5. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ...... 17 6. BACKGROUND AND RATIONALE ...... 18 6.1 INTRA-ABDOMINAL INFECTIONS...... 18 6.2 PROPERTIES OF ERAVACYCLINE ...... 19 6.3 CLINICAL EXPERIENCE ...... 20 6.3.1 Single Ascending Dose Study (TP-434-P1-SAD-1)...... 20 6.3.2 Multiple Ascending Dose Study (TP-434-P1-MAD-1)...... 21 6.3.3 Phase 2 Study in Subjects with cIAI (TP-434-P2-cIAI-1)...... 22 6.3.4 Summary of Known and Potential Risks...... 23 6.4 DOSING RATIONALE ...... 23 6.5 POPULATION TO BE STUDIED...... 24 6.6 STATEMENT OF COMPLIANCE...... 24 7. STUDY OBJECTIVES AND ENDPOINTS...... 24 7.1 PRIMARY OBJECTIVE...... 24 7.2 PRIMARY ENDPOINT...... 24 7.3 SECONDARY OBJECTIVES ...... 24 7.4 SECONDARY ENDPOINTS ...... 25 7.5 SAFETY PARAMETERS ...... 25 8. STUDY DESIGN...... 25 8.1 NUMBER OF SUBJECTS...... 25 8.2 STUDY DESIGN ...... 25 8.3 MEASURES TAKEN TO MINIMIZE BIAS ...... 26 8.4 EXPECTED DURATION OF SUBJECT PARTICIPATION...... 26 9. SELECTION AND WITHDRAWAL OF SUBJECTS ...... 27 9.1 INCLUSION CRITERIA FOR ENROLLMENT ...... 27 9.2 EXCLUSION CRITERIA...... 28 9.3 REQUALIFICATION FOR STUDY ENTRY ...... 30 9.4 SUBJECT WITHDRAWAL CRITERIA ...... 30 9.4.1 Early Discontinuation from Study Drug Administration...... 30 9.4.2 Withdrawal from Study Protocol...... 31 9.5 REPLACEMENT OF SUBJECTS ...... 31 9.6 PRIOR AND CONCOMITANT MEDICATION ...... 31 10. STUDY PROCEDURES ...... 32

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10.1 GENERAL PROCEDURES...... 32 10.1.1 Temperature ...... 32 10.1.2 Abdominal Examination...... 32 10.1.3 Safety Laboratory Tests ...... 32 10.1.4 ECGs...... 33 10.1.5 Microbiologic Specimen Collection ...... 33 10.1.6 Blood Cultures ...... 33 10.1.7 Radiologic Assessment ...... 33 10.1.8 Clinical Response...... 34 10.1.8.1 Clinical Cure ...... 34 10.1.8.2 Clinical Failure...... 34 10.1.8.3 Indeterminate ...... 34 10.1.8.4 Missing...... 34 10.2 TIME POINT SPECIFIC PROCEDURES ...... 34 10.2.1 Screening...... 34 10.2.2 Randomization and Enrollment of Subjects ...... 36 10.2.3 Day 1 (Dose Cycle 1)...... 36 10.2.4 Days 2 and 3 (Dosing Cycles 2 and 3)...... 37 10.2.5 Days 4 through 14 (Dosing Cycles 4 through 14) - while subject is on study drug ...... 37 10.2.6 End-of-Therapy (EOT), Test of Cure (TOC) and Follow-Up (FU)...... 38 10.3 STUDY DRUG ADMINISTRATION...... 38 10.3.1 Study Drug Infusions and Dosing Schedule ...... 38 10.3.2 Treatment Compliance...... 40 10.3.3 Guidance to Investigators for Determining When to End Therapy ...... 40 10.4 SPECIFIC RESTRICTIONS/REQUIREMENTS ...... 40 10.4.1 Avoidance of Pregnancy...... 40 10.4.1.1 Instructions for Male Subjects ...... 40 10.4.1.2 Instructions for Female Subjects...... 41 10.4.2 Pregnancy...... 41 10.4.2.1 Follow-up in the Event of a Pregnancy...... 41 10.5 STUDY DISCONTINUATION/TERMINATION CRITERIA...... 41 11. QUALITY CONTROL AND QUALITY ASSURANCE...... 42 11.1 QUALITY CONTROL ...... 42 11.1.1 Monitoring ...... 42 11.2 QUALITY ASSURANCE ...... 42 12. ASSESSMENT OF SAFETY...... 42 12.1 DEFINITIONS...... 42 12.1.1 Adverse Event...... 42 12.1.2 Adverse Drug Reaction (ADR)...... 43 12.1.3 Serious Adverse Event (SAE)...... 43 12.1.4 Unexpected Adverse Reactions ...... 44 12.2 AE COLLECTING AND REPORTING...... 44 12.3 GRADING OF ADVERSE EVENTS ...... 46 12.4 RELATIONSHIP TO STUDY DRUG...... 46

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12.5 LABORATORY TEST ABNORMALITIES...... 47 12.6 FOLLOW-UP OF ADVERSE EVENTS...... 47 13. EVALUATION OF EFFICACY ...... 47 13.1 ANALYSIS POPULATIONS...... 47 13.2 EFFICACY EVALUATIONS ...... 48 13.2.1 Clinical Response...... 48 13.2.2 Per Patient Microbiological Response...... 48 13.2.3 Per Pathogen Microbiological Outcomes ...... 49 13.2.3.1 Favorable...... 49 13.2.3.2 Unfavorable...... 49 14. STATISTICAL METHODS ...... 50 14.1 DATA COLLECTION,PROCESSING, AND REPORTING ...... 50 14.2 GENERAL METHODOLOGY ...... 50 14.2.1 Sample Size Considerations...... 51 14.3 INDEPENDENT DATA SAFETY MONITORING BOARD (DSMB) ...... 52 14.4 INTERIM ANALYSIS ...... 52 15. STUDY DRUG MATERIALS...... 52 15.1 STUDY DRUG NOMENCLATURE ...... 52 15.2 STUDY DRUG PREPARATION...... 53 15.2.1 Reconstitution ...... 53 15.2.2 Administration ...... 53 15.3 STUDY DRUG STORAGE...... 53 15.4 STUDY DRUG PACKAGING AND LABELING...... 54 15.5 STUDY DRUG COMPARATOR ...... 54 15.6 STUDY DRUG ACCOUNTABILITY ...... 54 15.7 STUDY DRUG HANDLING AND DISPOSAL ...... 54 15.8 BREAKING THE BLIND ...... 55 16. INVESTIGATOR REQUIREMENTS ...... 55 16.1 AE COLLECTION AND REPORTING...... 55 16.2 PROTOCOL ADHERENCE ...... 56 16.3 CASE REPORT FORMS...... 56 16.4 SOURCE DOCUMENT MAINTENANCE...... 56 16.5 STUDY MONITORING REQUIREMENTS ...... 56 16.6 STUDY COMPLETION ...... 56 17. PROTECTION OF HUMAN SUBJECTS AND GENERAL STUDY ADMINISTRATION ...... 57 17.1 INFORMED CONSENT ...... 57 17.2 IRB/IEC APPROVAL...... 57 17.3 SUBJECT DATA PROTECTION ...... 58 18. DATA MANAGEMENT AND MONITORING...... 58 18.1 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ...... 58

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18.2 RETENTION OF RECORDS...... 59 19. FINANCING AND INSURANCE...... 59 20. PUBLICATION POLICY...... 59 21. REFERENCES...... 60 Appendix 1: APACHE II Score...... 61 Appendix 2: Central Safety Laboratory Tests ...... 62 Appendix 3: Blood PK Sample Collection, Handling, Preparation and Shipping ...... 63 APPENDIX 4: INVANZ® PACKAGE INSERT ...... 64

List of Tables Table 1 Summary Statistics and PK Parameter Values (Means) for Eravacycline Using Noncompartmental Methods...... 21 Table 2 Pharmacokinetic Parameters Observed in Eravacycline IV Multiple Ascending Dose (Noncompartmental Analysis)...... 22 Table 3 Study Drug Infusion Scheme of a 24-h Dosing Cycle...... 26 Table 4 Timeline for Individual Study Subjects ...... 27 Table 5 Study Drug Infusion Specifications ...... 39

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4. LIST OF ABBREVIATIONS ADR Adverse Drug Reaction CV Coefficient of variation, Cardiovascular AE Adverse event CT Computed tomography AIDS Acquired Immune Deficiency Syndrome DG Dose group ALT Alanine aminotransferase dL Deciliter APACHE Acute Physiology and Chronic Health DSMB Data Safety Monitoring Board Evaluation APS Acute Physiology Score ECG Electrocardiogram AST Aspartate aminotransferase eCRF Electronic case report form AUC Area under the plasma concentration-time eg For example curve

AUC0-12 Area under the plasma concentration-time EMA European Medicines Agency curve from time zero to time 12-h

AUC0-24 Area under the plasma concentration-time EOT End of Therapy curve from time zero to time 24-h

AUC0-tau(ss) Area under the plasma concentration-time (6ȕ/ Extended-VSHFWUXPȕ-lactamase(s) curve from time zero to time tau over a dosing interval at steady state, where tau is the length of the dosing interval ƕ AUC0-inf Area under the plasma concentration-time F Farenheight curve from time zero to time infinity

AUC0-tau(ss) Area under the plasma concentration-time FDA Food and Drug Administration curve from time zero to time tau over a dosing interval at steady state, where tau is the length of the dosing interval B/P Blood pressure FU Follow-up ƕC Celcius gGram CD4 Cluster of differentiation 4: a glycoprotein GI Gastrointestinal tract that is found primarily on the surface of helper T cells CE Clinically evaluable GCP Good clinical practice CI Confidence interval GGT Gamma-glutamyl transferase cIAI Complicated intra-abdominal infection GMP Good manufacturing practices CK Creatine kinase GOT Glutamyl oxaloacetic transaminase CL Clearance h Hour(s)

Cmax Maximum observed plasma concentration HIV Human Immunodeficiency Virus CNS Central nervous system HR Heart Rate Conc Concentration IAI Intra-abdominal Infection CRA Clinical research associates IB Investigator’s Brochure CRF Case report form ICH International Conference on Harmonization CRO Contract Research Organization IDSA The Infectious Diseases Society of America

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ie In other words MITT Modified intent-to-treat IEC Independent Ethics Committee mMITT Microbiologic modified-intent-to-treat IND Investigational New Drug MRI Magnetic resonance imaging IRB Institutional Review Board N Number in a group ITT Intent-to-treat N/A Not applicable IV Intravenous ng Nanogram IWRS Interactive web-based response PD Pharmacodynamic system kg Kilogram PHI Protected health information L Liter PK Pharmacokinetics LAR Legally Authorized Representative qXh Every X hours LDH Lactic dehydrogenase RBC Erythrocyte count MAD Multiple ascending dose RR Respiration Rate Max Maximum SAD Single ascending dose MCH Mean cell hemoglobin SAE Serious adverse event MCHC Mean cell hemoglobin concentration SOA Schedule of Assessments MCV Mean cell volume SUSAR Suspected unexpected serious adverses reaction

ME Microbiologically evaluable T1/2 Elimination half-life MedDRA Medical Dictionary for Regulatory TBD To be determined Activities

μg Microgram Tmax Time to Cmax μmol Micromolar TOC Test-of-cure mg Milligram ULN Upper limit of normal MIC Minimum inhibitory concentration U.S. United States

MIC90 MIC of at least 90% of clinical Ȝ] Elimination rate constant isolates tested mL Milliliter WBC White blood cell (count) mm Hg Milimeter of mercury WHODrug World Health Organization Drug Dictionary Min Minutes, Minimum 0.45% NaCl 0.5x normal saline Micro-ITT Microbiological Intent-to-Treat Population

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5. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE SPONSOR: Tetraphase Pharmaceuticals, Inc. Sponsor’s Chief Medical Officer: 480 Arsenal Street, Suite 110 Patrick Horn, MD, PhD Watertown, MA 02472 | USA Phone: +1-617-715-3593 Phone: +1-617-715-3600 Mobile: +1-847-668-1044 Fax: +1-617-926-3557 E-mail: [email protected] CONTRACT RESEARCH ORGANIZATION: PSI CRO AG Baarerstrasse 113a 6300 Zug | Switzerland Medical Monitor for sites in Medical Monitor for sites in Europe, Argentina and the USA: South Africa, and India: Eric Batson, MD, PhD Julia Chebotareva, MD, PhD Mobile: +1 (206) 841 5001 Phone: +38 (044) 492 8560 x 4231 Fax: +1 (866) 894 6290 Mobile: +38 (067) 509 1771 Email: [email protected] Fax: +38 (044) 492 8565 Email: [email protected] CENTRAL LABORATORY: For Sites in Argentina and the USA: For Sites in Europe: Eurofins Medinet Washington DC Eurofins Medinet Breda 14100 Park Meadow Drive Bergschot 71 Chantilly, Virginia 20151 | USA P.O. Box 5510, 4801 DM Breda Phone: +1 866 324 8691 The Netherlands Fax: +1 703-480-2670 Phone: +31 (0)76 572 72 72 Fax: +31 (0)76 573 77 78 For Sites in South Africa: Eurofins Medinet South Africa For Sites in India: Drs. Dietrich, Voigt & Partners Eurofins Bangalore PathCare Clinical Trials Laboratory #183, Gayathri Tech Park PathCare Park 1st Floor, EPIP 2nd Phase Neels Bothma Street Whitefield, Bangalore-560066 N1-City | Goodwood 7460 Karnataka, India South Africa Phone: +91 80 3070 6687 Phone: +27 21 596 3587 Fax: +91 80 4168 0405 Fax: +27 21 596 3710

BIOANALYTICAL LABORATORY: Quotient Bio Analytical Sciences LGC Limited Newmarket Road Fordham, Cambridgeshire CB7 5WW | United Kingdom Phone: +44 (0) 1638 720 500

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6. BACKGROUND AND RATIONALE 6.1 Intra-abdominal Infections Complicated intra-abdominal infections (cIAIs) extend beyond the hollow viscus of origin into the peritoneal or retroperitoneal spaces and are associated with either abscess formation or peritonitis and systemic signs and symptoms of illness [1]. The management of cIAIs usually involves surgical removal of tissue and/or drainage in conjunction with the use of a broad- spectrum antibiotic or antibiotic combination [1]. cIAIs are a common problem in clinical practice and consume substantial hospital resources and costs. Despite the fact that a wide range of individual antimicrobial agents and combination of agents are available for use in cIAI, no regimen has been consistently demonstrated to be superior or inferior and there is obvious need for future research and better therapy.

The selection of antimicrobial therapy must cover a complex flora comprised of aerobic and anaerobic bacteria usually derived from the intestinal tract. Antibiotics used for the empiric treatment of cIAIs should have activity against enteric gram-negative aerobic and facultative bacilli and enteric gram-positive streptococci, staphylococci and enterococci. In addition, coverage for obligate anaerobic bacilli is recommended for distal small bowel, appendiceal, and colon-derived infections and for more proximal gastrointestinal perforations in the presence of obstruction or paralytic ileus [1].

A 2003 study [2] collecting over 5600 aerobic and facultative gram-negative bacilli isolated from intra-abdominal infections in 74 study centers globally found, depending on institution, resistance to fluoroquinolones (10-30%), cephalosporins (3-20%), aminoglycosides (0-23%), and near complete susceptibility to carbapenems. Enterobacteriaceae comprised 84% of all isolates and E. coli was the most frequenWLVRODWH  ([WHQGHGVSHFWUXPȕ-lactamases (6ȕL) were detected in 9% of E. coli, 14% of Klebsiella spp. and 14% of Enterobacter spp., and these isolates were generally more antibiotic resistant. Further, increased drug resistance was found to be associated with longer hospitalizations. Anaerobic bacteria were isolated from >80% of cases of cIAI, with Bacteroides spp., particularly B. fragilis, the most common isolate [3]. Resistance among the B. fragilis group is also on the rise with rates for clindamycin (20-35%), moxifloxacin (27-38%), cefoxitin (5-30%) and ampicillin-sulbactam (up to 17%) in the double digits [4]. In a recently completed Phase 2 study with eravacycline in cIAI [ ] using investigative sites in Eastern Europe, India and the U.S, 25% of the Gram-negative aerobes isolated from baseline intra-DEGRPLQDOFXOWXUHVZHUH(6ȕ/SURGXFHUVDQGZHUHHUWDSHQHP-resistant.

With the exception of carbapenem antibiotics, there are few classes of antibiotics with a sufficiently broad-spectrum to cover all the potential pathogens that the peritoneum is exposed to

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following a perforation of the intestinal tract. The carbapenems are losing traction due to carbapenemases and porin changes mediating resistance, even in enteric bacteria. Thus, there is a need for broad-spectrum antibiotics with the pharmacokinetics (PK) and pharmacodynamics (PD) to empirically cover the wide range of potential pathogens seen in cIAIs. Eravacycline has the in vitro potency and spectrum to cover the intestinal flora that commonly cause cIAIs.

6.2 Properties of Eravacycline Eravacycline is a novel fluorocycline tetracycline that inhibits bacterial protein synthesis by binding to the 30S-ribosomal subunit, blocking entry of aminoacyl-tRNA molecules into the A site of the ribosome, thus preventing incorporation of amino-acid residues into elongating peptide chains [6]. Importantly, eravacycline was designed to be active against the two major acquired tetracycline-specific resistance mechanisms: ribosomal protection where a protein mediates the removal of tetracycline from its binding site on the small ribosomal subunit and drug efflux [6, 7]. As a fluorocycline, eravacycline is impervious to either mechanism, with equivalent microbiological activity against E. coli strains expressing either resistant determinant. Further, ervacycline showed potent mechanism-based activity in a coupled transcription/translation assay ± the addition of Tet(M), a widespread ribosomal protection protein. Thus, eravacycline should be active where legacy tetracyclines doxycycline, minocycline, and tetracycline are not.

Eravacycline is highly active in vitro against emerging pathogens like Acinetobacter baumannii as well as clinically important species of Enterobacteriaceae (6ȕ/-producing and carbapenem- resistant strains of Escherichia coli and Klebsiella pneumoniae, Proteus spp., Providencia spp., Morganella morganii and Stenotrophomonas maltophilia) and anaerobes. Eravacycline is also active against enteric bacteria including Salmonella spp., Shigella spp., and tetracycline-resistant isolates harboring tetracycline-selective efflux pumps or a ribosomal protection resistance mechanism. Eravacycline may not exhibit high activity against Pseudomonas aerugonisa when it is the sole pathogen. The full description of the in vitro antibacterial activity of eravacycline can be found in the Investigator’s Brochure (IB). In subjects with higher risk for poor outcomes from infections [ie, auto-immune syndrome or Drug Reaction with Eosinophila and Systemic Symptoms (DRESS) syndrome] the investigator should carefully review the inclusion and exclusion criteria to ensure the appropriate enrollment of subjects. Clostridium difficile associated infections are seen with all antibiotics. Care should be taken in subjects enrolled in this clinical study, any subject that has signs or symptoms of Clostridium difficile (eg, diarrhea or abdomonial pain) should be evaluated for this infection.

In terms of gram-positive pathogens, eravacycline has activity against both nosocomial and community-acquired methicillin-susceptible or methicillin-resistant Staphylococcus aureus

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strains, vancomycin-susceptible or vancomycin-resistant Enterococcus faecium and Enterococcus faecalis, penicillin-susceptible or penicillin-resistant strains of Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus mitis, Streptococcus intermedius, Streptococcus anginosus, Streptococcus sanguis, and Streptococcus pyogenes. For cIAIs, enterococci and streptococci can be frequently isolated, and eravacycline consistently exhibits excellent activity against these strains.

One of the most frequently isolated anaerobic pathogens in cIAIs either as the sole pathogen or, often in conjunction with another gram-negative is Bacteroides fragilis. Eravacycline has a

minimum inhibitory concentration of at least 90% of clinical isolates tested (MIC90)against B. fragilis of 1 μg/mL (and is 4- to >16-fold more potent than comparators tigecycline and vancomycin). Eravacycline also has excellent activity against other Bacteroides spp. and a wide range of gram-positive and gram-negative anaerobes: Porphyromonas asaccharolytica, Prevotella spp., Peptostreptococcus anaerobius, Peptostreptococcus micros, Clostridium perfringens, Clostridium difficile, Anaerococcus spp., Propionibacterium acnes, Actinomyces spp., Finegoldia magna, Fusobacterium spp., Parabacteroides distasonis, and Peptoniphilus asaccharolyticus.

The high degree and reliability of in vitro antibacterial activity against multidrug-resistant gram- negative and gram-positive aerobic, facultative, and obligate pathogens and efficacy observed with eravacycline in established animal models of infection warrant clinical development of eravacycline as a single therapy treatment option for cIAIs and other serious bacterial infections.

6.3 Clinical Experience Intravenously administered eravacycline has been studied in two completed clinical trials in healthy subjects (a single dose study and a multiple dose study), and in a phase 2 study in subjects with cIAI. Please refer to the current IB for details of the eravacycline clinical studies and adverse event (AE) profile.

6.3.1 Single Ascending Dose Study (TP-434-P1-SAD-1) Dose escalations were performed sequentially using 56 healthy adult volunteers (18-50 years old). Seven Dose Groups (DGs) each consisting of 8 subjects, with 6 randomized to receive eravacycline and 2 to receive matching placebo were studied.

Plasma PK was dose-proportional and linear with respect to AUC and Cmax (Table 1). All estimated half-lives were between approximately 12 to 24-h, the 3 mg/kg DG had the largest

estimated T½, while the 0.10 mg/kg DG had the smallest.

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Table 1 Summary Statistics and PK Parameter Values (Means) for Eravacycline Using Noncompartmental Methods

Dose (mg/kg) Parameter 0.10 0.25 0.50 1.00 1.50 2.00 3.00

AUC0-inf QJÂKUP/ 557.18 1326.06 2721.96 5613.03 8983.82 12541.24 23518.39

Cmax (ng/mL) 227.00 466.50 993.50 1888.33 3233.33 4916.67 9793.33

T1/2 (h) 12.39 16.09 19.03 20.28 22.34 20.41 24.18

No serious adverse events (SAEs) were reported. Gastrointestinal side effects were observed at • 2 mg/kg. Local site reactions were observed at the infusion sites in 6 subjects. No clinically significant safety lab values or significant changes in ECG readings were observed in any dose group.

6.3.2 Multiple Ascending Dose Study (TP-434-P1-MAD-1) A total of 32 healthy adult volunteers, 6 randomized to receive eravacycline and 2 to placebo per DG, received one of the following for 10 days: ƒ 30 minute infusions of 0.50 mg/kg q24h (DG1) ƒ 30 minute infusions of 1.50 mg/kg q24h (DG2) ƒ 60 minute infusions of 1.50 mg/kg q24h (DG3) ƒ 60 minute infusions of 1.0 mg/kg q12h (DG4) Exposure at steady state (0 to 24-h) was largest for DG4 and smallest for DG1 as the mean

AUC0-24(ss) was 12688.88 ngÂh/mL (AUC was doubled since PK is linear and steady state was UHDFKHG DQGQJÂh/mL for the two groups, respectively. The mean maximum plasma

concentration was largest for DG2 and smallest for DG1 as the mean Cmax after the first dose of study drug was 3403.33 ng/mL and 931.33 ng/mL, respectively.

The time to maximum plasma levels was shorter for DG1 and DG2, which had median Tmax of

0.50 hs. The median Tmax for DG3 and DG4 was 1.25 h and 1.00 h, respectively. The mean half-life on Day 10 was longest for DG4 at 38.19 h and shortest for DG3 at 29.34 h. A summary of the PK parameters for each dosing group on Day 10 using noncompartmental analysis is summarized in Table 2.

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Table 2 Pharmacokinetic Parameters Observed in Eravacycline IV Multiple Ascending Dose (Noncompartmental Analysis) Arithmetic Mean (%CV) Median (Range) for Tmax DG 1 DG 2 DG 3 DG 4* Parameter (0.50 mg/kg,q24h, (1.50 mg/kg, q24h, (1.50 mg/kg, q24h, (1.00 mg/kg, q12h, 30 min infusion) 30 min infusion 60 min infusion) 60 min infusion)

AUC0-tau(ss) QJÂh/mL) 2931.89 (30.35) 8124.79 (18.97) 7858.17 (11.53) 6344.44 (14.88)

Cmax (ng/mL) 931.33 (16.58) 3403.33 (9.34) 1891.67 (10.25) 1825.00 (15.53)

Tmax (h) 0.50 (0.50 – 0.50) 0.50 (0.25 – 2.00) 1.25 (0.50 – 1.32) 1.00 (1.00 – 1.00)

Ȝz (1/h) 0.0227 (35.84) 0.0212 (0.0123) 0.0243 (18.26) 0.0197 (31.05)

T1/2 (h) 35.54 (49.56) 34.99 (31.79) 29.34 (18.88) 38.19 (33.76) Key: AUC0-tau(ss) = area under the plasma concentration-time curve from time zero to time tau over a dosing interval at steady state, where tau is the length of the dosing interval; Cmax= maximum observed plasma concentration; DG = dose group; T1/2 = elimination half-life; Tmax =time to Cmax; Ȝz = elimination rate constant; min = minute *AUC over 12-h instead of 24-h in DGs 1-3

No SAEs were reported. The most common AEs were mild to moderate and when classified by system organ class were gastrointestinal (nausea and vomiting), administration site, and vascular disorders (superficial phlebitis). Infusion site AEs (pain, discomfort, edema, and superficial phlebitis) were more frequent in subjects receiving higher doses and appeared to be more common when IV access was in smaller, more peripheral veins.

No clinically significant safety laboratory values or significant changes in ECG readings were observed.

6.3.3 Phase 2 Study in Subjects with cIAI (TP-434-P2-cIAI-1) This was a double-blind, randomized multicenter study evaluating the safety and efficacy of two dose regimens of eravacycline compared to ertapenem in the treatment of subjects with cIAI. One hundred forty-three (143) subjects were randomized into one of 3 treatment arms; eravacycline 1.5 mg/kg q24-h (56 subjects), eravacycline 1.0 mg/kg q12-h (57 subjects) or ertapenem 1 g q24h (30 subjects).

The primary efficacy endpoint was clinical outcome at the Test of Cure (TOC) visit in the microbiologically evaluable (ME) population (subjects who received study drug, had a clinical outcome at TOC recorded, and had at least one baseline bacterial pathogen isolated from the initial intra-abdominal culture). All treatment arms had excellent cure rates that were statistically similar. The cure rates (% and 95% CI) in the ME population at the TOC visit were 92.9 (80.5- 98.5), 100 (91.4-100), and 92.3 (74.9 – 99.1) for the eravacycline 1.5 mg/kg q24-h, the eravacycline 1.0 mg/kg q12-h, and ertapenem 1 g q24h groups, respectively. Secondary efficacy endpoints included clinical outcomes at the End of Therapy (EOT), TOC and Follow-up (FU) visits for all populations as well as microbiological outcomes calculated on a per subject or a per

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pathogen basis. All secondary efficacy endpoints supported the primary endpoint. The outcomes in the 3 treatment arms for all endpoints were excellent and statistically similar.

There were no serious adverse events that were considered by the investigator to be related to study drug, and there were no new safety signals for eravacycline identified in this study. Overall, treatment emergent adverse events were reported by 35.8%, 28.6% and 26.7% of subjects in the eravacycline 1.5 mg/kg q24-h, the eravacycline 1.0 mg/kg q12-h and the ertapenem 1 g q24-h groups, respectively. Nausea was reported by 1.9%, 10.7%, and 6.7%; emesis by 5.7%, 1.8% and 0%, in the eravacycline 1.5 mg/kg q24-h, the eravacycline 1.0 mg/kg q24-h and the ertapenem 1 g q24-h groups, respectively. The incidence of phlebitis was 1.9% and 3.6% in the eravacycline 1.5 mg/kg q24-h and the eravacycline 1.0 mg/kg q12-h groups, respectively. These rates are much lower than those observed in the phase 1 studies, presumably resulting from the decreased concentration and prolonged infusion times used in the phase 2 study.

6.3.4 Summary of Known and Potential Risks Eravacycline is related to tetracyclines, a well-known class of antibiotics that has been utilized for over 50 years. The overall risk to the subjects of the present study is deemed to be acceptable, as indicated by the results of the nonclinical toxicology program, the initial phase 1 studies and the phase 2 study. As expected for this class of antibiotics, transient gastrointestinal adverse events of mild to moderate intensity were observed at the higher dose levels in the phase 1 studies. Low levels of nausea and emesis were observed in the cIAI phase 2 study. Infusion site related adverse events, including pain, discomfort and superficial phlebitis, were observed in the phase 1 MAD study. The eravacycline concentration was reduced by 25-50% in the phase 2 study, and the reported incidence of infusion site related adverse events was greatly reduced. Based upon the observed safety and tolerability profile, the broad spectrum of antimicrobial activity, and the results of both dosage regimens of eravacycline used in the phase 2 study, the use of eravacycline in the current study is expected to be efficacious. Please refer to the latest version of the eravacycline IB and the Invanz® package insert for additional information on eravacycline and ertapenem, respectively. 6.4 Dosing Rationale Two doses of eravacycline were evaluated in the phase 2 study based on tolerability and steady- state AUCs achieved in healthy volunteers in the phase 1 MAD study, and the clinical reponse rates for both doses were similar to the comparator, ertapenem. For this current study, the

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eravacycline 1.0 mg/kg (up to a maximum of 150 mg) q12-h dose has been selected, since this dose provided higher AUCs with no increase in safety or tolerability issues. The comparator, ertapenem, was chosen because it is approved by the FDA and other regulatory authorities for the treatment of cIAI. The once daily administration of ertapenem allows for a convenient dosing schedule in this double-blinded study. It will be given at the recommended dose of 1 g q24-h for an expected minimum of four 24-h dosing cycles. 6.5 Population To Be Studied Approximately 536 acutely hospitalized subjects with a diagnosis of cIAI requiring surgery will be recruited into this study. 6.6 Statement of Compliance This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), and applicable regulatory and Institutional Review Board (IRB) / Independent Ethics Committee (IEC) requirements.

7. STUDY OBJECTIVES AND ENDPOINTS 7.1 Primary Objective The primary objective of this study is to compare the clinical response at the test-of-cure (TOC) visit in the microbiological intent-to treat (micro-ITT) population for subjects in the 2 treatment arms.

7.2 Primary Endpoint The primary endpoint of this study will be the clinical response at the TOC visit in the micro-ITT population.

NOTE: For the EMA, the primary analysis populations will be the all-treated (MITT) and the clinically evaluable (CE) populations.

7.3 Secondary Objectives The secondary objectives of the study are to: ƒ Compare the clinical response for subjects in the 2 treatment arms at the end-of-treatment (EOT), TOC, and follow-up (FU) visits in the following populations: - Intent-to-treat (ITT) population - All-treated (MITT) population - Clinically evaluable (CE) population - Micro-ITT population (for EOT, FU) - Microbiologically evaluable (ME) population

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ƒ Compare the microbiologic response for subjects in the treatment arms at the EOT and TOC visits in the following populations: - Micro-ITT population - ME population ƒ Assess the safety and tolerability of eravacycline administration in the safety population ƒ Explore pharmacokinetic (PK) parameters after eravacycline infusion, including:

- Cmax, Tmax, AUC0-12

7.4 Secondary Endpoints The secondary endpoints of the study are: ƒ Clinical response at the EOT, TOC, and FU visits ƒ Microbiologic response for subjects in the 2 treatment arms at the EOT and TOC visits

7.5 Safety Parameters The parameters that will be used to assess safety in this study include: o Physical exam including vital signs o Adverse events o ECGs at specified time points o Safety labs at specified time points 8. STUDY DESIGN 8.1 Number of Subjects The planned study enrollment is approximately 536 subjects. For this study, enrollment occurs at the time of randomization, and it is expected that more subjects will be screened than enrolled into the study. This sample size was calculated as described in section 14.2.1 based on the expectation that 75% of subjects will have a baseline pathogen identified and be included in the micro-ITT population. An assessment of the actual number of subjects in the micro-ITT population will be made following completion of the 400th subject. If there is less than the expected proportion of subjects in the micro-ITT population, the sample size will be increased as needed to provide a sufficient number of evaluable subjects.

A maximum of 30% of the total subjects enrolled may come from India.

8.2 Study Design This is a phase 3, randomized, double-blind, double-dummy, multicenter, prospective study to assess the efficacy, safety, and PK of eravacycline compared with ertapenem. Dosing in the study arms is described in the table below.

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Table 3 Study Drug Infusion Scheme of a 24-h Dosing Cycle Initial Dose Follow-up Dose STUDY DRUG Bag 1 Bag 2 Bag N/A 60 min infusion 30 min infusion 60 min infusion Eravacycline, 1.0 mg/kg q12h Eravacycline Placebo Eravacycline Ertapenem, 1 g q24h Placebo Ertapenem Placebo

All subjects will remain hospitalized for the complete course of drug therapy.

8.3 Measures Taken to Minimize Bias Subjects will be assigned to study drug regimens using computerized randomization. Except for the responsible study site pharmacist or designee, and separate unblinded clinical research associates (CRAs) to monitor drug supply and adherence to study drug blinding and randomization procedures, all study staff and participants will be blinded to the IV dosing regimens of subjects.

8.4 Expected Duration of Subject Participation The study will last approximately 6-8 weeks. Foreseen treatment duration at study entry is expected to be a minimum of four 24-h dosing cycles, (ie, in accordance with IDSA Guidelines and the Schedule of Assessments (SOA) for study drug administration). However, study drug may be discontinued at the discretion of the investigator at any time. Study drug treatment should be stopped when symptoms of cIAI have resolved, there is treatment failure, or the maximum allowed number of 14 dosing cycles has been reached. A review of subjects requiring longer than 7 dosing cycles is required with the Medical Monitor. (Refer to Section 10.3.3 Guidance to Investigators for Determining When to End Therapy).

The TOC evaluation will be conducted 25-31 calendar days after the first dose of study drug is administered and a follow-up visit will be performed 38-50 calendar days after the first dose of study drug is administered.

The individual subject study timeline is shown in Table 4.

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Table 4 Timeline for Individual Study Subjects END-OF- STUDY DRUG TEST-OF-CURE FOLLOW-UP SCREENING ENROLLMENT THERAPY TREATMENT (TOC) (FU) (EOT) Within 48-h of Day 1 (Dose Cycle 1) Within 24-h of Day 25-31 Day 38-50 First Dose through EOT Last Dose Establish diagnosis Use IWRS* to Infuse study drug, Review of subjects Return to study Return to study of complicated randomize to either: with Medical center for center for intra- study drug Monitor for assessment of assessment of abdominal therapies longer microbiological microbiological x Eravacycline IV infections (cIAI) than seven 24-h and clinical and clinical 1.0 mg/kg (up to dosing cycles. response and response and a maximum of Verify eligibility safety safety 150 mg) q12-h, for enrollment EOT assessments OR should be performed at x Ertapenem IV 1 premature g q24h withdrawal or Expected 4 (min) treatment failure to 14 (max) study and within 24-h of drug treatment 24- last dose. h dosing cycles.

*IWRS = Interactive Web-based Response System

9. SELECTION AND WITHDRAWAL OF SUBJECTS

9.1 Inclusion Criteria for Enrollment Subjects must meet all of the following criteria: 1. Male or female subject hospitalized for cIAI with one of the following diagnoses: a. Intra-abdominal abscess: one or more abscesses surrounding diseased or perforated viscera b. Gastric or intestinal perforation associated with diffuse peritonitis c. Peritonitis due to perforated viscus, or other focus of infection (but not spontaneous bacterial peritonitis associated with cirrhosis and chronic ascites) d. Appendicitis with perforation, peritonitis or abscess e. Cholecystitis with perforation or abscess f. Intra-abdominal abscess (single or multiple), including hepatic and splenic abscesses g. Peritonitis (local or diffuse) Note: infections limited to the hollow viscus, such as simple cholecystitis and simple appendicitis, are not eligble. Ischemic bowel disease without perforation is not eligible. Acute suppurative cholangitis and acute necrotizing pancreatitis are not eligible 2. At least 18 years of age (and not over 65 years of age for subjects in India) 3. Evidence of a systemic inflammatory response with at least one of the following: a. Fever (oral, rectal, tympanic, or by temportal artery WHPSHUDWXUH!Û)Û& Rr hypothermia (temperature ” 95.9Û)/ 35.5Û&

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b. Elevated WBC (> ULN laboratory range); or proportion of band forms of the WBC differential beyond the ULN laboratory range c. Increased pulse (HR > 90 beats per minute) d. Increased respiratory rate (> 20 breaths per minute) 4. Abdominal pain or flank pain (with or without rebound tenderness), or pain caused by cIAI that is referred to another anatomic area such as back or hip, or localized or diffuse abdominal wall rigidity, or mass, or ileus 5. Able to provide informed consent. 6. If male: must agree to use an effective barrier method of contraception during the study and for 30 days following the last dose if sexually active with a female of childbearing potential. 7. If female: a. Not pregnant or nursing b. If of childbearing potential, will commit to either: i. Use at least two medically accepted, effective methods of birth control (eg, condom, oral contraceptive, indwelling intrauterine device, hormonal implant /patch, injections, approved cervical ring) during study drug dosing and for 30 days following last study drug dose ii. Sexual abstinence

And either

8A. Meets All Inclusion Criteria for Pre-operative Enrollment: ƒ Has a sonogram or radiographic imaging result congruent with the diagnosis of cIAI, AND ƒ Acute surgical or percutaneous intervention (open laparotomy, laparoscopic surgery, or percutaneous drainage of an abscess) is foreseen within 48-h 8B. Meets All Inclusion Criteria for Intra-operative/Post-operative Enrollment: ƒ Visual confirmation of cIAI (presence of pus within the abdominal cavity), AND ƒ Surgical intervention includes open laparotomy, laparoscopic surgery, or percutaneous draining of an abscess, AND ƒ Intervention is adequate (ie, a procedure in which all communications between the GI tract and the peritoneal cavity are closed, no necrotic intestine is left, and all infected collections are drained at the procedure)

9.2 Exclusion Criteria Subjects must NOT meet any of the following exclusion criteria: 1. Considered unlikely to survive the 6-8 week study period x Any rapidly-progressing disease or immediately life-threatening illness, including acute hepatic failure, respiratory failure and septic shock

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x Requirement for vasopressors (prior to enrollment) at therapeutic dosages (ie, dopamine > 5 μg/kg/min, any dose of norepinephrine, epinephrine or phenylephrine) to maintain a systolic blood pressure t 90 mm Hg or a mean arterial pressure t 70 mm Hg following adequate fluid resuscitation 2. Renal failure as defined as: a. Threefold increase of serum creatinine to a known previous value, OR b. Decrease in estimated glomerular filtration rate to < 75% of a known previous value, OR c. Urine output of < 0.3 mL/kg per h for > 24-h, OR d. Anuria for > 12-h, OR e. Serum creatinine of > 4 mg/dL (353.6 μmol/L) with an acute rise of 0.5 mg/dL (42.2 μmol/L) compared with a previous value, OR f. Creatinine clearance < 50 mL/min as estimated by the Cockcroft-Gault equation, OR [݈݁ܽ݉݁ܨ ݂݅ ݋݀ݕ ܹ݄݁݅݃ݐ [݇݃] × [0.85ܤ × ([ݏݎݕ] ݁݃ܣെ 140) ݁ܥ [݉ܮ/݉݅݊]= [ܮ݀ ݐ݅݊݅݊݁ [݉݃Τܽ݁ݎܥ ݑ݉ݎ݁ܵ × ஼௥ 72 g. Requires peritoneal dialysis, hemodialysis or hemofilration 3. Presence or possible signs of significant hepatic disease: a. Alanine aminotransferase or aspartate aminotransferase > 3 x upper limit of normal (ULN); > 5 x ULN for patients with hepatic abscess, OR b. Total bilirubin > 3 x ULN, unless isolated hyperbilirubinemia is directly related to the acute process, OR c. Alkaline phosphatase > 3 x ULN, OR d. Subjects with diagnosis of hepatic failure 4. Immunocompromised condition, including known HIV positivity (requiring anti-retroviral therapy or with CD4 count < 300), AIDS, organ (bone marrow) transplant recipients, and hematological malignancy. Immunosuppressive therapy, including use of high-dose corticosteroids (eg, > 40 mg prednisone or equivalent per day for greater than 2 weeks) 5. History of moderate or severe hypersensitivity reactions to tetracyclines, carbapenems, ȕ- lactam antibiotics or to any of the excipients contained in the study drug formulations 6. Participation in any investigational drug or device study within 30 days prior to study entry 7. Known or suspected current central nervous system (CNS) disorder that may predispose to seizures or lower seizure threshold (eg, severe cerebral arteriosclerosis, epilepsy) 8. Previously received eravacycline in a clinical trial 9. Antibiotic-related exclusions: a. Receipt of effective antibacterial drug therapy for cIAI for a continuous duration of > 24-h during the 72-h preceding enrollment (however, subjects with documented cIAI (ie, known baseline pathogen) who have received at least 72-h of antibiotic therapy and are considered treatment failures may be enrolled. Treatment failure is defined as persistent

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fever and/or clinical symptoms; or the development of a new intra-abdominal abscess after • 72-h of antibiotic therapy), OR b. Receipt of ertapenem or any other carbapenem, or tigecycline for the current infection, OR c. Need for concomitant systemic antimicrobial agents other than study drug 10. Refusal of mechanical ventilation, dialysis or hemofiltration, cardioversion or any other resuscitative measures and drug/fluid therapy at time of consent 11. Known or suspected inflammatory bowel disease or associated visceral abscess 12. The anticipated need for systemic antibiotics for a duration of more than 14 days 13. Systemic malignancy that required chemotherapy, immunotherapy, radiation therapy or antineoplastic therapy within the previous 3 months or which is anticipated to begin prior to the TOC visit 14. Known at study entry to have cIAI caused by a pathogen(s) resistant to one of the study drugs 9.3 Requalification for Study Entry Subjects not fulfilling the entry criteria may not be re-screened for participation even if their eligibility characteristics have changed, with the exception of serum creatinine. Serum creatinine is the only screening parameter that can be retested in the establishment of eligibility. Volume depleted subjects should first receive volume replacement prior to having their creatinine clearance calculated.

9.4 Subject Withdrawal Criteria Subjects should be encouraged to complete all study evaluations. However, subjects may withdraw consent to participate in this study at any time without penalty or loss of benefits to which the subject is otherwise entitled.

Every reasonable effort should be made to determine the reason a subject discontinues treatment and/or withdraws prematurely from the study and this information should be recorded on the appropriate page(s) of the eCRF.

9.4.1 Early Discontinuation from Study Drug Administration If a subject prematurely discontinues from study drug treatment, every reasonable effort should be made to adhere to future protocol evaluations and examinations as specified in the SOA.

If a subject has been discharged from the hospital and refuses to return to the investigational site for scheduled evaluations, but is willing to undergo follow-up investigations, safety data and concomitant medication information may be collected by telephone and/or through medical records. The reason for early study drug treatment withdrawal should be recorded on the

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appropriate page(s) of the eCRF. Reasons for withdrawal from study drug treatment may include, but are not limited to, the following:

1. Occurrence of an AE, which, in the opinion of the investigator, warrants the subject’s permanent withdrawal from study treatment. In the event of withdrawal due to the occurrence of an AE, the regional medical monitor must be notified within 24-h. Subjects withdrawn secondary to an ongoing non-serious AE (regardless of relationship to study drug) or SAE that is not related to study drug treatment must be followed clinically until the follow-up safety visit (Day 38-50). Subjects withdrawn secondary to an ongoing study drug-related SAE must be followed clinically until resolution or stabilization 2. Insufficient therapeutic effect requiring alternative systemic antibacterial treatment for the current IAI 3. Need for concomitant systemic antibacterial therapy for an infection other than the current IAI 9.4.2 Withdrawal from Study Protocol Subjects who wish to withdraw from study drug treatment should be encouraged to complete the TOC and FU visits after their last study drug administration. If they choose to withdraw from the study completely, the reason for withdrawal should be recorded on the appropriate page(s) of the eCRF. Reasons for withdrawal from the study may include, but are not limited to, the following:

1. Significant subject noncompliance, defined as refusal or inability to adhere to the prescribed dosing and follow-up regimens 2. Subject lost to follow-up 3. At the request of the subject, investigator, or study sponsor

9.5 Replacement of Subjects Subjects who are randomized will not be replaced.

9.6 Prior and Concomitant Medication Prior administration of systemic antibacterial agents is allowed only in the following circumstances:

< 24-h of continuous antibacterial drug therapy for cIAI during the 72-h preceding enrollment: however, subjects with documented cIAI (ie, known baseline pathogen) who have received at least 72-h of systemic antibiotic therapy and are considered treatment failures may be enrolled. Treatment failure is defined as persistent fever and/or clinical symptoms; or the development of a new intra-abdominal abscess after • 72-h of antibiotic therapy

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The following concomitant medications are or are not permitted while on study therapy: x Valproic acid and divalproex sodium x No concomitant systemic antibacterials are permitted after the initial dose of study medication until the completion of the FU visit. Subjects who require concomitant systemic antibacterials must be withdrawn from study drug and will be considered treatment failures from the time of initiation of non-study antibiotics.

All other concomitant medications necessary for the health and wellbeing of a subject will be permitted. All concomitant medications will be recorded on the appropriate eCRF page.

10. STUDY PROCEDURES Please also review the entire protocol, including the Schedule of Assessments and appendices, for additional details. 10.1 General Procedures 10.1.1 Temperature Temperatures should be recorded orally, rectally, aurally using a tympanic thermometer, or by temporal artery. Axillary temperatures are not allowed. 10.1.2 Abdominal Examination A thorough clinical examination of the abdomen is to be performed at specified time points. Specific abdominal assessment findings such as abdominal pain, tenderness to palpation, rebound tenderness, guarding, mass, and ascites will be assessed and severity graded as none, mild, moderate or severe according to the following definitions: None: No signs or symptoms Mild: Awareness of signs and symptoms, but easily tolerated Moderate: Signs or symptoms of enough intensity to cause interference with usual activity Severe: Signs and symptoms of enough intensity that incapacitate and interfere with usual activity Other pertinent findings should be recorded, including inability to tolerate oral or enteral intake and presence or absence of ileus.

The clinical abdominal examination will include an assessment of the surgical wound (if applicable). The surgical wound examination will assess signs of infection such as skin erythema, induration, tenderness, warmth to touch, fluctuance, swelling and superficial wound pain. If signs of infection are present, findings will be recorded and graded as mild, moderate or severe according to the definitions above. If present, the nature of any discharge (eg purulent, serous, bloody, etc.) will be assessed and the drainage cultured if clinically indicated. 10.1.3 Safety Laboratory Tests Safety laboratory tests for this study (chemistry, hematology, coagulation, and urinalysis) are to be performed by a central laboratory, and only values from the central laboratory are to be

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entered into the laboratory section of the study database. Values from local laboratories may be used to determine eligibility for study enrollment and as the basis for clinical decisions. See Appendix 2 for the complete list of safety laboratory tests. 10.1.4 ECGs Standard 12-lead ECGs are to be recorded with the subject in the supine position when indicated by the protocol. 10.1.5 Microbiologic Specimen Collection Appropriate aerobic and anaerobic specimens for culture at the time of the initial surgical procedure (or during re-intervention in the case of prior treatment failures) should be collected from the site of infection by aspiration and/or tissue sample and directly inoculated into culture media during the surgical intervention; microbiologic specimens collected during routine operative care prior to subject consent may be used for study purposes. For subjects that enter the study as a documented cIAI treatment failure (ie, with a known baseline pathogen), reasonable attempts should be made to provide the baseline isolates to the central laboratory. The specimens should be representative of the material associated with the clinical infection. Samples collected by swabs are allowed only if it is not possible to collect aspirated fluid or tissue samples; samples collected from abdominal drains are not allowed. These specimens will be cultured and the species will be identified by the local or regional laboratory. All purified isolate(s) will be sent to a central, reference laboratory at time points determined by the Sponsor for confirmation of species identification and susceptibility analysis to eravacycline and ertapenem. Specific instructions for sample collection, processing, and shipment can be found in the laboratory manual(s) for this study.

10.1.6 Blood Cultures A set of blood cultures (aerobic and anaerobic) should be taken from at least two separate venipuncture sites at Screening before the initiation of study drug. Upon knowledge of a positive culture for a pathogen, blood cultures should be repeated until sterile (ie, both sets of cultures from two separate venipuncture sites are negative for pathogens) through the EOT visit. If baseline cultures are negative, follow up cultures should be obtained only if clinically indicated (eg, worsening of signs and symptoms, relapse, or new infection). Specific instructions for sample collection, processing, and shipment can be found in the laboratory manual(s) for this study.

10.1.7 Radiologic Assessment Radiologic evaluation may be performed as part of the pre-operative diagnosis or if surgical re- intervention is clinically indicated. Copies of all radiographic study reports will be collected and copies of the films or images may be requested as deemed necessary by the Sponsor.

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10.1.8 Clinical Response Clinical outcome assessments will be made at the EOT, TOC and FU visits. Clinical responses will be classified as Clincal Cure, Clinical Failure, Indeterminate or Missing based on clinical outcomes. A favorable clinical response is “Clincal Cure”.

Cure, failure, and indeterminate are the clinical response categories as defined below.

10.1.8.1 Clinical Cure Clinical Cure is defined as complete resolution or significant improvement of signs or symptoms of the index infection such that no additional antibacterial therapy, surgical, or radiological intervention (eg, an ultrasound guided drainage) is required. Routine imaging procedures (eg, an investigational ultrasound) are not considered radiological interventions.

10.1.8.2 Clinical Failure Subjects are classified as a Clinical Failure based on:

ƒ Death related to cIAI at any time point ƒ Persistence of clinical symptoms of cIAI ƒ Unplanned surgical procedures or percutaneous drainage procedures ƒ Post-surgical would infections requiring systemic antibiotics ƒ Initiation of rescue antibacterial drug therapy for cIAI

Clinical Failures are to be documented by obtaining an appropriately performed wound or deep site culture, if feasible.

10.1.8.3 Indeterminate If the subject’s outcome is neither Clinical Cure nor Clinical Failure then the outcome should be listed as “Indeterminate.” The reason for an “Indeterminate” designation must be provided.

10.1.8.4 Missing Study data are listed as “Missing” if the Investigator did not complete an assessment or if the subject was not present for the study visit.

10.2 Time Point Specific Procedures 10.2.1 Screening All potential study participants will undergo a screening evaluation. Clinical assessments and local laboratory results performed during the subject’s hospitalization (within 48-h of screening) may be used to establish eligibility. If any of the required screening assessments defined below were not performed, they must be performed prior to determining eligibility. Screening may occur on the first day of dosing and will include the following activities:

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1. Obtain a signed informed consent: Procedures performed as standard of care prior to signing the informed consent may be used to determine eligibility. Informed consent must be obtained prior to performing any study specific procedures that are not standard of care; however microbiologic specimens collected during routine operative care prior to subject consent may be used for study purposes. 2. Clinical assessments: ƒ Complete pertinent medical history including approximate time of onset and type of symptoms related to current condition (eg, abdominal pain, past surgeries, allergies, and known viral/bacterial diseases) ƒ Complete physical examination; including, temperature, resting vital signs, height and weight. ƒ Abdominal examination ƒ 12-lead ECG ƒ Prior and concomitant medication assessment: record both day and time for all antibiotics administered in the preceding 72-h 3. Laboratory Assessments: ƒ Safety Laboratory Tests (chemistry, hematology, coagulation, urinalysis) ƒ Calculate creatinine clearance (Cockcroft-Gault formula): [݈݁ܽ݉݁ܨ ݂݅ ݋݀ݕ ܹ݄݁݅݃ݐ [݇݃] × [0.85ܤ × ([ݏݎݕ] ݁݃ܣെ 140) ݁ܥ [݉ܮ/݉݅݊]= [ܮ݀ ݐ݅݊݅݊݁ [݉݃Τܽ݁ݎܥ ݑ݉ݎ݁ܵ × ஼௥ 72 4. Serum pregnancy test (women of childbearing potential only) NOTE: If a serum pregnancy test is not available at the investigator site then a urine pregnancy test may be utilized locally. 5. APACHE II assessment ƒ Serum bicarbonate can be used in place of arterial blood gases for the completion of the APACHE II assessment. 6. Microbiological assessments: ƒ Obtain specimens for culture and in vitro susceptibility testing of all aerobic and anaerobic organisms considered to be pathogens from the following sites: - Site of infection during surgical intervention (should be taken with direct inoculation of sample into culture media) - Blood cultures - Extra-abdominal/wound cultures (if applicable) Specific instructions for sample collection, processing, and shipment can be found in the laboratory manual(s) for this study. 7. Radiologic Assessment (at Investigator’s discretion): Perform a radiologic evaluation as part of the pre-operative diagnosis (computed tomography (CT) scan, ultrasound, and/or magnetic resonance imaging (MRI) scan),

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with or without contrast. Radiologic confirmation of cIAI is required in order for a subject to qualify for pre-operative enrollment. Copies of all operative procedure notes, diagnostic study reports, as well as reports associated with percutaneous drainage procedure will be collected. 8. Determine eligibility

10.2.2 Randomization and Enrollment of Subjects Once an informed consent is obtained and study eligibility is established, a blinded study site member will obtain a subject number and a study drug assignment for each subject from a computer-generated randomization coding scheme using an interactive web-based response system (IWRS). Randomization to eravacycline (1.0 mg/kg q12h) or ertapenem (1 g q24h) treatment arms will occur in a 1:1 ratio. For this study, enrollment is considered to occur at the time a subject is randomized. Randomization will be stratified based on primary sites of infection (ie, complicated appendicitis versus all other cIAI diagnoses). No more than approximately 30% of subjects enrolled should have complicated appendicitis.

The study will include approximately 100 sites. No site should enroll more than 35 subjects. Each investigative site should enroll no more than 1 complicated appendicitis subject for every 3 subjects enrolled into the study at their site. A site specific change to the ratio of ‘complicated appendicitis: other cIAI diagnoses’ or to the total number of subjects that may be enrolled may be granted by the Sponsor in order to complete study enrollment.

10.2.3 Day 1 (Dose Cycle 1) The calendar day on which the first study drug infusion of the first 24-h dosing cycle is administered is Day 1. If Day 1 (Dose Cycle 1) and Screening occur on the same day, the resting vital signs, abdominal examination, and safety laboratories do not need to be repeated.

1. Assessments prior to the First Study Drug Administration: ƒ Record temperature ƒ Resting vital signs ƒ Safety Laboratory tests (chemistry, hematology, coagulation, urinalysis) ƒ Abdominal examination ƒ AE assessment ƒ Concomitant medication assessment ƒ PK sampling in accordance with SOA and Appendix 3 ƒ Blood cultures (if indicated) 2. IV Study Drug Infusions ƒ Study drug administration per dosing schedule 3. Assessments after the First Study Drug Administration:

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ƒ PK sampling in accordance with SOA and Appendix 3 ƒ Resting vital signs ƒ Temperature every 8-h ƒ AE assessment ƒ Concomitant medication assessment 4. Radiologic evaluation (if deemed necessary by the investigator)

10.2.4 Days 2 and 3 (Dosing Cycles 2 and 3) The following will be performed on both Days 2 and 3 (Dosing Cycles 2 and 3) 1. Clinical Assessments: ƒ Temperature every 8-h ƒ Resting vital signs ƒ Abdominal examination ƒ AE assessment ƒ Concomitant medication assessment 2. Laboratory Assessments: ƒ Safety Laboratory tests (chemistry, hematology) ƒ Blood cultures (if indicated) ƒ Intra-/extra-abdominal cultures (if indicated) 3. IV Study Drug Infusions ƒ Study drug administration per dosing schedule. 4. Radiologic evaluation (if deemed necessary by the investigator)

10.2.5 Days 4 through 14 (Dosing Cycles 4 through 14) - while subject is on study drug 1. Clinical Assessments: ƒ Temperature every 8-h ƒ Daily resting vital signs while subject is hospitalized ƒ Daily abdominal examination ƒ AE assessment ƒ Concomitant medication assessment ƒ Evaluate subject’s requirement for continuation of study drug 2. Laboratory Assessments: ƒ Safety laboratory tests (chemistry, heamatology) on Day 4 (Dosing Cycle 4) and repeated every 3 dosing cycles while subject is on IV study drug ƒ Blood cultures (if indicated) ƒ Intra-/extra-abdominal cultures (if indicated) 3. IV Study Drug Infusions x Study drug administration per dosing schedule

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4. Radiologic evaluation (if deemed necessary by the investigator)

10.2.6 End-of-Therapy (EOT), Test of Cure (TOC) and Follow-Up (FU) The EOT, TOC, and FU procedures are to be performed at premature withdrawal or treatment failure and within 24-h of the last dose of study drug, 25-31 days after the initial dose of study drug, and 38-50 days after the initial dose of study drug, respectively. 1. Clinical Assessments: ƒ Complete physical examination, including temperature and resting vital signs ƒ Abdominal examination ƒ Clinical response assessment ƒ AE assessment ƒ 12-lead ECG at EOT visit only ƒ Concomitant medication assessment ƒ Radiologic evaluation (if deemed necessary by the investigator) 2. Laboratory Assessments: ƒ Safety laboratory tests - Chemistry and hematology at the EOT, TOC and FU visits - Coagulation and urinalysis at EOT visit only ƒ Serum pregnancy test (women of childbearing potential only) NOTE: If a serum pregnancy test is not available at the investigator site then a urine pregnancy test may be utilized locally. ƒ Blood culture (if indicated) ƒ Intra-/extra-abdominal cultures if indicated

10.3 Study Drug Administration 10.3.1 Study Drug Infusions and Dosing Schedule Both eravacycline and ertapenem, when prepared for infusion, are colored solutions. The two drugs require different infusion volumes. The dosing interval for ertapenem is every 24-h. For eravacycline, the dosing interval is every 12-h. For these reasons, this study has been designed using double-dummy methodology.

During each 24-h dosing cycle, the subject will receive three infusions. For the first 24-h dosing cycle, the first two of these infusions (to be administered sequentially) are collectively called Dose 1, and the third infusion is called Dose 2. Dose 1 is comprised of two IV infusion bags, called Bag 1 and Bag 2. The third infusion bag in a 24-h period is called Bag N/A. The make up of Dose 1 (Bags 1 and 2) and Dose 2 (Bag N/A) is shown in the table below. Subsequent 24-h

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dosing cycles are similar, but dose numbers are consecutive [the second 24-h dosing cycle includes Dose 3 (Bags 1 and 2) and Dose 4 (Bag N/A), etc.].

Table 5 Study Drug Infusion Specifications TREATMENT ARM INFUSION Eravacycline Ertapenem 1.0 mg/kg q12h 1 g q24h Dose 1 final volume (mL)a wt(kg) ÷ 0.3 wt(kg) ÷ 0.3 drug Eravacycline Placebo Bag 1 amount (mg)b wt(kg) x 1.0 N/A conc (mg/mL)c 0.3 N/A infusion time (min)d 60 ± 10 60 ± 10 final volume (mL) 60 60 drug Placebo Ertapenem Bag 2 amount (mg) N/A 1000 conc (mg/mL) N/A 16.7 infusion time (min) 30 ± 5 30 ± 5 Dose 2 final volume (mL)a wt(kg) ÷ 0.3 wt(kg) ÷ 0.3 drug Eravacycline Placebo Bag N/A amount (mg) b wt(kg) x 1.0 N/A conc (mg/mL)c 0.3 N/A infusion time (min)d 60 ± 10 60 ± 10 a Final infusion volume per bag must not exceed 500 mL b Maximum dose of eravacycline per infusion is not to exceed 150 mg c Concentration may be decreased as long as the total infusion volume does not exceed 500 mL d Infusion time may be increased to 120 minutes per IV bag All solutions for infusion will be prepared by an unblinded pharmacist or designee. Specific instructions for preparation of study drugs are included in the Pharmacy Manual for this study.

The amount of eravacycline administered during any given 24-h dosing cycle is not to exceed 300 mg (ieHDFKLQIXVLRQPXVWEH”PJRIHUDYDF\FOLQH).

The eravacycline-matched placebo will consist of sterile 0.5x normal saline (0.45% NaCl). The ertapenem-matched placebo will consist of sterile normal saline (0.9% NaCl).

{Dose 1, Bag 2} will be started immediately following the completion of {Dose 1, Bag 1} and collection of the PK sample. {Dose 2, Bag N/A} will be started 12-h following the start of {Dose 1, Bag 1}. The 12-h interval between doses can be reduced by up to 2 hours in each of the 3 initial 24-h dosing cycles (ie, 10 h after the preceding study drug infusion time point) to allow for a more practical infusion schedule for the duration of therapy. After the third 24-h dosing cycle, the allowable administration window is q12h ± 1 h.

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10.3.2 Treatment Compliance The date, start and stop times, and volumes used in each infusion of study drug, will be recorded. These detailed records will be used to document compliance with the eravacycline and ertapenem dosing regimens/dosing cycles.

If an infusion administration is inadvertently delayed, must be started as soon as possible. No infusion should be “missed” regardless of how long it may have been delayed.

Subjects will be considered compliant with study drug treatment if they do not miss more than 20% of the expected study drug infusions, as defined by interval of first and last dose.

10.3.3 Guidance to Investigators for Determining When to End Therapy In accordance with guidelines, subjects are expected to remain on study drug treatment for a minimum of four 24-h dosing cycles (unless subject is a treatment failure or cure) and for a maximum of 14 dosing cycles. Study drug treatment should be continued until resolution of infection signs and symptoms is documented, such as: ƒ Maximum temperature (oral, rectal, tympanic, or by temportal artery) has been < Û)Û&IRU-h ƒ Improvement of abdominal signs and symptoms presenting at study entry ƒ A return of bowel function and restoration of oral/enteral intake Any subject requiring longer than seven 24-h dosing cycles of study drug therapy should be discussed with the Medical Monitor. A subject who continues to require antibacterial therapy for the current infection beyond 14 dosing cycles will be considered a treatment failure.

10.4 Specific Restrictions/Requirements Study drug must only be administered while subjects are hospitalized. All subjects must have an EOT assessment, and return to investigational sites for TOC and FU assessments unless they have withdrawn consent.

10.4.1 Avoidance of Pregnancy

10.4.1.1 Instructions for Male Subjects There is no information on the effects of eravacycline on the development of the fetus in humans. Therefore, it is important that the partners of male subjects do not become pregnant during the study and for a total period of 30 days after the male subject has received the last dose of study drug. Subjects should avoid fathering a child by either being abstinent or only engaging in intercourse if two medically accepted, effective methods of birth control (eg, condom, oral contraceptive,

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indwelling intrauterine device, hormonal implant/patch, injections, and approved cervical ring) are used.

Since there is a risk of drug being secreted in the ejaculate, subjects (including men who have had vasectomies) whose partners are currently pregnant should use barrier methods for the duration of the study and for two weeks afterwards. This is to ensure that the fetus is not exposed to the investigational product in the ejaculate.

10.4.1.2 Instructions for Female Subjects

Females of childbearing potential are eligible for enrollment in this study. There is no information on the effects of eravacycline on the development of the fetus in humans. Therefore, it is important that female subjects enrolled into the study do not become pregnant during the study and for a total period of 30 days after the subject has received the last dose of study drug.

10.4.2 Pregnancy

Pregnancy is considered an immediately reportable event (but not an adverse event), and the investigator will record information concerning the pregnancy on the appropriate form and submit it to the Medical Monitor within 24-h of learning of a subject’s pregnancy. Study drug administration will be stopped in any female subject who becomes pregnant while participating, and the subject will be followed to determine the outcome of the pregnancy. All pregnancies in the female partners of male subjects receiving at least one dose of eravacycline will be recorded from first dose to 30 days after the final dose.

10.4.2.1 Follow-up in the Event of a Pregnancy The ethics committee and the Sponsor will be informed of all pregnancies in study subjects and in partners of male subjects.

The subject will be asked to provide information on the outcome of the pregnancy, including premature termination should the case arise. Spontaneous miscarriages and congenital abnormalities will be reported as serious adverse events (SAEs). Information on the status of the mother and child will be forwarded to the Medical Monitor or designee. Generally, follow up will be in accordance with regulatory guidance and at least 6-8 weeks after the estimated delivery date. Any premature termination of the pregnancy will be reported.

10.5 Study Discontinuation/Termination Criteria The study Sponsor reserves the right to terminate this clinical study or participation of an investigative site at any time. Reasons for termination may include, but are not limited to, the following:

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1. Incidence and/or severity and composition of AEs in this or other studies indicate a potential health hazard to subjects 2. Sponsor’s decision to discontinue investigation in a specific therapeutic area 3. Subject enrollment is unsatisfactory 4. An investigator requests to withdraw from participation 5. Serious and/or persistent noncompliance by the investigator with the protocol, clinical research agreement, Form FDA 1572, or applicable regulatory guidelines in conducting the study 6. IRB/IEC decision to terminate or suspend approval for the investigation or an investigator

11. QUALITY CONTROL AND QUALITY ASSURANCE

11.1 Quality Control 11.1.1 Monitoring The Sponsor, or designee(s), will monitor the study for compliance to the protocol, applicable laws and regulations, and Good Clinical Practice. The monitor(s) will verify data on the electronic case report form versus source data. The monitor is also responsible for ensuring that the proper records are maintained. Monitoring reports will be issued for each monitoring visit.

11.2 Quality Assurance Quality assurance personnel may audit the clinical trial sites and/or study-related materials at any time during the study.

12. ASSESSMENT OF SAFETY Safety will be assessed through AEs, physical examinations, vital signs, ECGs, and the collection of central laboratory data (ie, chemistry, hematology, coagulation, and urinalysis). The Principal Investigator and designated study staff are responsible for detecting, documenting and reporting events that meet the definition of an AE or SAE.

12.1 Definitions

12.1.1 Adverse Event An adverse event is any adverse experience in a subject administered a pharmaceutical product, whether or not it is considered drug-related, that occurs during a subject’s study participation (defined as after the time of initial informed consent). This would include any side effect, injury, toxicity, sensitivity reaction, intercurrent illness, or sudden death. A pre-existing condition is one that is present at study entry and is reported as part of the subject’s medical history. It should be reported as an AE if the frequency, intensity, or character of the condition worsens during study drug treatment. Subjects should be instructed to report all AEs to the investigator or study staff. Adverse events must be appropriately documented in the subject’s original source

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documents and entered into the eCRF. Investigators should report syndromes rather than list symptoms.

12.1.2 Adverse Drug Reaction (ADR) An adverse drug reaction (ADR) is any untoward and unintended response in a subject to an investigational medicinal product which is related to any dose administered to that subject.

12.1.3 Serious Adverse Event (SAE) A serious adverse event (SAE) is any AE, occurring at any dose and regardless of causality that:

x Results in death. x Is life-threatening. Life-threatening means that the subject was at immediate risk of death from the reaction as it occurred (ie, it does not include a reaction which hypothetically might have caused death had it occurred in a more severe form). x Requires inpatient hospitalization or prolongation of existing hospitalization. Hospitalization admissions and/or surgical operations scheduled to occur during the study period, but planned prior to study entry, are not considered AEs if the illness or disease existed before the subject was enrolled in the trial, provided that it did not deteriorate in an unexpected manner during the study (eg, surgery performed earlier than planned). x Results in persistent or significant disability/incapacity. Disability is defined as a substantial disruption of a person’s ability to conduct normal life functions. x Is a congenital anomaly/birth defect. x Is an important medical event. An important medical event is an event that may not result in death, be life-threatening, or require hospitalization but may be considered an SAE when, based upon appropriate medical judgment, it may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed in the definitions for SAEs. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.

Clarification should be made between the terms “serious” and “severe” since the terms ARE NOT synonymous. The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor medical significance (such as a severe headache). This is NOT the same as “serious,” which is based on subject/event outcome or action criteria described above, and is usually associated with events that pose a threat to a subject’s life or functioning. A severe AE does not necessarily need to be considered serious. For example, persistent nausea of

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several hours duration may be considered severe nausea but not an SAE. On the other hand, a stroke resulting in only a minor degree of disability may be considered mild, but would be defined as an SAE based on the above noted criteria. Seriousness (not severity) serves as a guide for defining regulatory reporting obligations.

Events that result from lack of efficacy of study drug, (ie, treatment failure, eg, ongoing cIAI’s, wound infections requiring antibiotics, recurrence of abcesses,) are not considered SAE’s and prolonged hospitalization etc. for these events will not be considered SAE’s.

12.1.4 Unexpected Adverse Reactions An adverse reaction is ‘unexpected’ if its nature and severity are not consistent with the information about the medicinal product in question set out in the most recent Investigator’s Brochure relating to the trial in question or the product information for ertapenem.

12.2 AE Collecting and Reporting All AEs spontaneously reported by the subject and/or in response to an open question from study personnel or revealed by observation, physical examination or other diagnostic procedures will be recorded on the appropriate page of the eCRF starting from the time of initial informed consent. Any clinically relevant deterioration in laboratory assessments or other clinical findings is considered an AE and must be recorded on the appropriate pages of the eCRF starting from the time of initial informed consent. When possible, signs and symptoms indicating a common underlying pathology should be noted as one comprehensive event.

All SAEs that occur during the course of the study, as defined by the protocol, must be reported by the Investigator to the Sponsor or its pharmacovigilance designee/CRO within 24-h from the point in time when the Investigator becomes aware of the SAE. In addition all SAEs, including all deaths, which occur from the time of signing of the informed consent up to and including 30 days after administration of the last dose of study drug, must be reported to Tetraphase or its designated CRO within 24-h. All SAEs and deaths must be reported whether or not considered causally related to the study drug. The information collected will include a minimum of the following: Subject number, a narrative description of the event and an assessment by the Investigator as to the intensity of the event and relatedness to study drug. Follow-up information on the SAE may be requested by Tetraphase or its representative CRO. Detailed instructions for the collecting and reporting of SAEs will be provided in the Investigator Site File.

If there are serious, unexpected adverse drug reactions associated with the use of the study drug, Tetraphase or its designated CRO will notify the appropriate regulatory agency(ies) and all participating Investigators on an expedited basis (7 days for fatal or life-threatening serious, unexpected adverse drug reactions). Tetraphase has delegated the responsibility to promptly

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notify the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) of all unexpected serious adverse drug reactions involving risk to human subjects in accordance with the rules and regulations of the IRB/IEC to the Principal Investigator.

An unexpected event is one that is not reported in the Investigator’s Brochure.

Reporting of SAEs and SUSARs

All SAEs must be reported to the designated CRO within 24-h of the investigational site’s knowledge of the occurrence. Each investigational site will submit the SAE information to the CRO.

The SAE information transmitted to the CRO will include the following (as available): ƒ Subject ID, investigator name, and site number ƒ SAE information: event term, onset date, severity, and casual relationship ƒ Basic demographic information (eg, age, gender, weight, et cetera) ƒ The outcomes attributable to the event [eg, death, a life-threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, other important medical event(s)] ƒ A summary of relevant test results, pertinent laboratory data, and any other relevant medical history ƒ The first and last dates of study drug administration ƒ A statement whether study drug was discontinued or study drug administration schedule was modified ƒ A statement whether event recurred after reintroduction of study drug if administration had been discontinued or withheld ƒ Supplemental information may include the following hospital records: laboratory results, radiology reports, progress notes, admission and emergency room notes, holding/observation notes, discharge summaries, autopsy reports, and death certificates The SAE information should be transmitted within 24-h with as much of the above information as available at the time. Supplemental information may be transmitted and should not delay the initial transmission. The Sponsor or CRO may contact the investigational site to solicit additional information or follow-up on the event. Investigational sites will be provided with detailed instructions on the procedures for transmitting SAEs to the CRO.

For regulatory purposes, initial reports of serious adverse drug reactions should be transmitted within the prescribed time frame as long as the following minimum information is available: subject identification, suspect study drug, reporting source, and an event or outcome that can be identified as being both serious and unexpected for which, in the investigator’s opinion, there is a suspected causal relationship.

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A suspected unexpected serious adverse reaction (SUSAR) which is fatal or life-threatening must be reported to the competent authority and ethics committee immediately (within 7 days) after the Sponsor becomes aware of the event. Any additional information must be reported within eight days of sending the first report.

A SUSAR which is not fatal or life-threatening must be reported to the competent authority and ethics committee as soon as possible (within 15 days) after the Sponsor becomes aware of the event.

All SUSARs occurring at the site will be entered into the European database established in accordance with Article 11 of the EU Clinical Trials Directive [8].

12.3 Grading of Adverse Events The severity of each AE will be categorized using the following criteria:

Grade 1 AE usually transient and requires no special treatment and does not interfere with Mild the subject’s daily activities. Grade 2 AE produces a low level of inconvenience to the subject and may interfere with Moderate daily activities. These events are usually ameliorated by simple therapeutic measures. Grade 3 AE interrupts daily activity and requires systemic drug therapy or other medical Severe treatment. Grade 4 AE places the subject, in the view of the investigator, at immediate risk of death Life-threatening from the reaction as it occurred (ie, it does not include a reaction that, had it occurred in a more severe form, might have caused death) Grade 5 AE resulted in death of the subject Death

12.4 Relationship to Study Drug

For each reported AE, the investigator must make an assessment of the relationship of the event to the study drug using the following scale:

Not Related: An event that is definitely not associated with study drug administration and is judged clearly due to causes other than the study drug.

Unlikely Related: An event that follows a temporal sequence from administration of the study drug, such that, a relationship is not likely and could be reasonably explained by the subject's clinical state, or other modes of therapy administered to the subject.

Possibly Related: An event that follows a reasonable temporal sequence from administration of the study drug, but that, may be due to another cause and could also be reasonably explained by the subject's clinical state, or other modes of therapy administered to the subject.

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Probably Related: An event that follows a reasonable temporal sequence from administration of the study drug, that is not easily explained by another cause (such as, known characteristics of the subject’s clinical state or other treatment) and is confirmed by improvement on stopping or slowing administration of the study agent (ie, de-challenge, if applicable).

Definitely Related: An event that is clearly associated with study drug administration.

In the event of death, the cause of death should be recorded as the AE. “Death” is an outcome and is NOT the AE. The only exception is “sudden death” when the cause is unknown.

12.5 Laboratory Test Abnormalities All central laboratory data generated by the study will be included in standard SAS datasets. Throughout this study, subjects will have samples sent to local laboratories and to the central laboratory. Only the values from the samples sent to the central laboratory will be captured in the laboratory values database and used for the safety analysis. Investigators may report AEs based upon local laboratory values. In this event, the actual value and the normal range for the local laboratory should be recorded on the AE form.

12.6 Follow-up of Adverse Events All AEs (regardless of relationship to study drug) and SAEs determined not to be study drug related (ie, not related and unlikely related) will be followed through the follow-up visit and be noted as “continuing” if not resolved at this visit. Any SAE that is determined to be study drug related (possibly, probably, or definitely related) will be followed to resolution or stabilization.

The outcome of AEs will be rated as: x Recovered/Resolved x Recovering/Resolving x Not Recovered/Not Resolved x Recovered/Resolved with Sequelae x Fatal x Unknown

13. EVALUATION OF EFFICACY 13.1 Analysis Populations The following definitions will be used in assigning subjects into study populations: x Intent-to-treat (ITT) population – all subjects who are randomized x Microbiological intent-to-treat (micro-ITT) population – all randomized subjects who have baseline bacterial pathogens that cause cIAI and against at least one of which the investigational drug has in vitro antibacterial activity

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x Clinically evaluable (CE) – all subjects who meet the definition for the ITT population and have no major protocol deviations x Microbiologically evaluable (ME) – all subjects who meet the definition for the micro- ITT population and have no major protocol deviations

13.2 Efficacy Evaluations The primary efficacy evaluation, clinical response at the TOC visit, will be conducted in the micro-ITT population.

The following secondary evaluations will be performed:

ƒ Clinical response at EOT, TOC, and FU visits in the following populations: - ITT - CE - Micro-ITT (EOT and FU) - ME ƒ Microbiologic responses at EOT and TOC visits in the following populations: - Micro-ITT - ME ƒ PK parameters after eravacycline infusion, including

- Cmax, Tmax, AUC0-12

13.2.1 Clinical Response Clinical outcome assessments will be made at the EOT, TOC and FU visits. Clinical responses will be classified as Clincal Cure, Clinical Failure, Indeterminate, or Missing based on clinical outcomes. A favorable clinical response is “Clincal Cure”.

13.2.2 Per Patient Microbiological Response The per subject microbiological response will be determined by the per pathogen microbiological outcomes.

An overall microbiological response will be assessed as “favorable” or “unfavorable” for each subject. For subjects from whom only one pathogen is isolated, the overall microbiological response will be based on the assessment for that pathogen. For subjects from whom more than one pathogen is isolated, the overall microbiological response will reflect the worst outcome present amongst all baseline pathogens. Favorable microbiological responses are “eradication” or “presumptive eradication”.

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13.2.3 Per Pathogen Microbiological Outcomes All bacterial isolates cultured from aerobic and anaerobic specimens will be evaluated for susceptibility to study drugs and the emergence of resistance and overgrowth of non-susceptible organisms.

Microbiological response categories are eradication, presumptive eradication, persistence acquiring resistance, presumed persistence, superinfection, new infection, indeterminate, or assessment not possible because of protocol deviation.

13.2.3.1 Favorable Eradication: Absence of causative organism from an appropriately obtained specimen at the site of infection at each time-point

Presumptive eradication: Absence of material to culture in a subject who has responded clinically to treatment

13.2.3.2 Unfavorable Persistence acquiring resistance: Continued presence of the original pathogen in cultures from the original site of infection obtained during or upon completion of therapy, and the pathogens that are susceptible, moderately susceptible, or intermediate in response to study drug pretreatment become resistant to study drug.

Presumed persistence: Repeat cultures are not obtained because of the absence of material to culture in a subject who is given additional antibiotics to treat the study entry IAI or no isolate is culturable.

Superinfection: Emergence of a new pathogen during therapy, either at the site of infection or at a distant site, with emergence or worsening of signs and symptoms of infection.

New infection: Eradication of the original pathogen followed by replacement (at the same site and after completion of therapy) by a new species, or by a new serotype or biotype of the same organism.

Indeterminate: Entry culture either not obtained or no baseline pathogen identified.

Assessment not possible because of protocol deviation: Any other circumstance that makes it impossible to define the microbiological response.

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14. STATISTICAL METHODS A detailed Statistical Analysis Plan will be used to guide the analysis and reporting of data collected in this study.

14.1 Data Collection, Processing, and Reporting All data collected in this study will be presented in data listings and, where indicated, tabulated in summary tables. Data will be presented and summarized using the SAS System (SAS Institute Inc, Cary, NC).

All AEs will be coded using the Medical Dictionary of Regulatory Activities (MedDRA) using all 5 levels of the MedDRA structure. Verbatim descriptions of AEs will be mapped to Preferred Terms and System Organ Classes using MedDRA and tabulated by treatment arm. The number and percentage of subjects who experience treatment-emergent AEs and serious AEs (SAEs) will be presented by reporting levels for System Organ Class and Preferred Term. Tabulations by severity and by relationship to study drug, as reported by the investigators, will also be provided. Concomitant medications will be coded using WHODrug Dictionary. MedDRA and WHODrug Dictionary version numbers will be specified in the Statistical Analysis Plan.

Hematology, chemistry, and where applicable, urinalysis data will be summarized using shift tables based on the upper and lower limits of the normal range, change from baseline, and the number and percentage of subjects with clinically notable values. Clinically notable values will be specified in the Statistical Analysis Plan.

Physical examination, including resting vital signs and ECG findings will be reported (as warranted) and analyzed as AEs.

eCRFs will be completed for all randomized subjects. Demography and end of study pages will be completed for subjects who are randomized but not treated.

An IWRS system will be used to allocate treatment assignments to subjects. Creation and validation of the clinical database, data entry, data management, and transfer of central laboratory data will be conducted in accordance with 21 CFR Part 11 and the Guidance for Industry on Computerized Systems Used in Clinical Trials.

14.2 General Methodology Continuous variables will be summarized with the number of observations, mean, standard deviation, median, minimum, and maximum.

Categorical variables will be summarized with frequencies and percentages. Percentages will be based on non-missing data unless specified otherwise.

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Clinical response rates will be determined, along with 95% CIs, for each treatment arm overall and each of the randomization strata (ie, primary site of infection). The clinical response rate will be determined as the number of subjects with Clinical Cure (ie, complete or significant improvement of signs or symptoms such that no further systemic antibiotic treatment is required) at the respective visit divided by the number of subjects in the analysis population (ie, overall or by randomization strata). A 95% CI around the difference in the eravacycline and ertapenem response rates will be used to determine if eravacycline is non-inferior to ertapenem. The methodology that will be used will be specified in the statistical analysis plan.

Per pathogen and per subject microbiological response rates will be determined, along with 95% CIs, by treatment arm. The per pathogen microbiological response rate will be determined as the number of subjects with a favorable response (ie, eradication or presumptive eradication) at the respective visit divided by the number of subjects in the analysis population with that pathogen at baseline. The per subject microbiological response rate will be determined as the number of subjects with a favorable response (ie, eradication or presumptive eradication) at the respective visit divided by the number of subjects in the analysis population.

Time to event data will be summarized using Kaplan-Meier methodology.

Unless specified otherwise, “Baseline” is defined as the closest value prior to the start of treatment with study drug.

Subjects who are randomized within the wrong strata will be identified in a data listing. For summaries based on the randomization stratification, all subjects will be summarized in the stratum that reflects their true primary site of infection, regardless of the strata in which they were randomized.

14.2.1 Sample Size Considerations This study is designed to demonstrate non-inferiority of 1.0 mg/kg q12h eravacycline to ertapenem, and a 10% non-inferiority margin will be used to determine success. A non- inferiority trial with a one-sided alpha of 0.025, 80% power, a non-inferiority margin (delta) of 10%, and projected response rates of 85% for both arms would need 201 subjects per arm in the micro-ITT population. A sample size of approximately 536 randomized subjects should provide sufficient numbers for this study, assuming 75% of enrolled subjects will meet the requirements for inclusion in the micro-ITT population.

For the EMA, a 12.5% non-inferiority margin will be used to determine success. In this case, using the same assumptions of response rate (85%) and eligibility (75%) and powering the study at 80%, the two-sided alpha is 0.008.

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The estimations of cure rates and numbers of subjects in the micro-ITT population come from the recent phase 2 study with eravacycline in cIAI in which ertapenem was used as the comparator. The study enrolled 143 subjects; 113 (79.0%) would qualify for the micro-ITT population as defined for this phase 3 study. One population analyzed for secondary efficacy endpoints in the phase 2 study was the microbiologic modified-intent-to-treat (mMITT) population. This population corresponds very closely with the micro-ITT population that will be used in the phase 3 study. The cure rates in the m-MITT population in the phase 2 study were 87.2% and 88.9% for eravacycline 1.0 mg/kg q12h and ertapenem 1.0g q24h, respectively.

14.3 Independent Data Safety Monitoring Board (DSMB)

A DSMB will be established to periodically review safety data (unblinded) from all subjects and advise the Sponsor regarding the continuing safety of current participants and those yet to be recruited.

The DSMB will have access to the following safety data:

ƒ Incidence of AEs (overall and drug-related) ƒ Listing of SAEs ƒ Premature discontinuations from study drug due to an AE ƒ Safety laboratory data

The DSMB may be provided with additional data if requested.

A charter of the board, comprised as a separate document, will be available prior to the first meeting. Recommendations from the DSMB will be made in writing and provided to the Sponsor after each data review. The board will recommend continuation, modification, or termination of the study.

14.4 Interim Analysis No interim analysis is planned for this study.

15. STUDY DRUG MATERIALS 15.1 Study Drug Nomenclature TP-434 is the active ingredient in eravacycline drug product. The chemical name of TP-434-046 (bis HCl salt form) is: [(4S,4aS,5aR,12aS)-4-(dimethylamino)-7-fluoro-3,10,12,12a- tetrahydroxy-1,11-dioxo-9-(2-(pyrrolidin-1-yl)ethanamido)-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide]bis-hydrochloride. The molecular formula for the free base is

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C27H31FN4O8, and the molecular weight is 558.56. Eravacycline is a yellow to orange solid that is soluble in water.

15.2 Study Drug Preparation 15.2.1 Reconstitution All study medications will be prepared for IV infusion by an unblinded pharmacist or his/her designee. Detailed instructions for the preparation of study drug are provided in the Pharmacy Manual for this study.

The eravacycline drug product will be reconstituted using sterile WFI and will be diluted using 0.45% NaCl. Reconstituted eravacycline should be a “clear yellow solution” with no visible particulates in the vial. Once WFI is added to eravacycline vials, swirl each vial gently until the drug dissolves completely (it should take approximately 1 to 2 minutes to achieve a clear yellow solution).

The ertapenem drug product will be prepared by the unblinded pharmacist according to the instructions in the Invanz® package insert and will use Water for Injection (WFI) for reconstitution and normal saline for dilution.

The unblinded pharmacist or his/her designee will provide the investigator with ready-to-use blinded infusion solutions for administration at scheduled study drug infusion times. It is the responsibility of the pharmacist/designee to maintain the blind of the infusion solutions.

15.2.2 Administration In the event of discomfort and/or pain due to infusion, the following actions can be taken at the Investigators’ request:

For Bag 1 and Bag N/A of any infusion (in the following recommended order): x Decrease concentration (as long as total volume does not exceed 500 mL) x Increase length of infusion to 120 minutes per IV bag

For Bag 2 of any infusion: x Follow standard of care and Invanz® package insert

15.3 Study Drug Storage Eravacycline vials containing solid sterile drug product should be stored at -20qC. Ertapenem vials containing solid sterile drug product should be stored at ” 25°C, and not frozen. For further details, please consult the Pharmacy Manual.

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15.4 Study Drug Packaging and Labeling Packaging: ƒ Eravacycline See sections 15.2.1, 15.2.2, and 15.3. Eravacycline will be packaged according to current GMP and GCP guidelines. ƒ Ertapenem Ertapenem for IV administration will be supplied in bulk in the original vials, which will be repackaged for the purposes of the study. Ertapenem will be provided with study specific labeling. Purchased and repackaged ertapenem will be packaged according to current GMP and GCP guidelines.

Labeling: The study medication will be labeled according to the requirements of local law and legislation as well as current GMP and GCP guidelines. Proof labels, detailing actual label text, will be available in the study files of all participating countries.

15.5 Study Drug Comparator Ertapenem is a carbapenem antibiotic that has been approved for the treatment of cIAI. The recommended dose is 1 g q24-h for this indication. Please consult the local prescribing product information for important information regarding warnings, precautions and AEs reported with the use of this product.

15.6 Study Drug Accountability It is the responsibility of the unblinded pharmacist to ensure that a current record of inventory/drug accountability is maintained. Inventory records must be readily available for inspection by the unblinded study monitor and are open to inspection by the FDA or other regulatory authorities at any time. Each shipment of drug supply for the study will contain an Investigational Drug Transmittal and Receipt Form to assist the unblinded pharmacist in maintaining current and accurate inventory records.

Upon receipt of the investigational drug, the pharmacist or designee will visually inspect the shipment and verify the number and condition of vials received. The information will also be entered into the IWRS system.

15.7 Study Drug Handling and Disposal Upon the completion or termination of the study, and upon written authorization from Tetraphase, or its representative, all unused and/or partially used study drug must be destroyed at

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the investigative site or returned to a central drug depot, as instructed by the Sponsor or Sponsor representative. It is the investigator’s responsibility to ensure that Sponsor, or its representative, has provided written authorization that procedures for proper disposal of the study drug have been established, and that appropriate records of the disposal are documented and maintained.

15.8 Breaking the Blind The study drug treatment assignment will be unblinded only in emergency situations when knowledge of the treatment received is absolutely necessary for management of the subject or when it is in the best interest of the subject. The investigator has unrestricted and immediate access to unblind the treatment code in the eCRF system. The instructions for unblinding a subject in the eCRF system can be found in the “eCRF Completion Guidelines.”

In the event unblinding is necessary, the investigator is encouraged but not required to contact the appropriate Medical Monitor to discuss the situation and the subject’s medical status.

When a subject’s treatment assignment is unblinded, a comprehensive source note must be completed by the unblinding investigator that includes the date and time and the reason(s) the subject’s treatment code was unblinded. In the event the investigator chooses to discuss the unblinding with the Medical Monitor, the source note must also include a record of the discussion.

It is mandatory that all personnel who are involved in the unblinding and who have access to the unblinded treatment assignment information maintain the confidentiality of the information by not divulging the randomization code.

16. INVESTIGATOR REQUIREMENTS 16.1 AE Collection and Reporting The Investigator’s responsibilities include the following: ƒ Monitor and record all AEs, including SAEs, regardless of the severity or relationship to study treatment ƒ Determine the seriousness, relationship and severity of each event ƒ Determine the onset and resolution dates of each event ƒ Monitor and record all pregnancies and follow up on the outcome of the pregnancy ƒ Transmit SAE information to the designated CRO within 24-h of the study site staff becoming aware of new information ƒ Ensure all AE and SAE information are supported by documentation in the subjects’ medical records ƒ Report SAEs to local ethics committees, as required

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16.2 Protocol Adherence Each investigator must adhere to the protocol as detailed in this document and agree that any changes to the protocol must be approved by the Sponsor prior to seeking approval from the IRB/IEC. Each investigator will be responsible for enrolling only those subjects who have met the protocol inclusion and exclusion criteria, or must have obtained prior approval from the Medical Monitor for deviations from the criteria. The Sponsor or the Sponsor’s representative reserves the right to close sites where the protocol is not being followed or there is not a timely input of data into eCRFs. Investigative sites may be prematurely terminated from further study participation if the subjects they enroll have a significantly low ME evaluability rate or who do not recruit at least 1 subject per quarter.

16.3 Case Report Forms Electronic CRFs will be supplied by the Sponsor, or its representative, for the recording of all study data as specified by this protocol. eCRFs should be handled in accordance with instructions from the Sponsor, or its representative. eCRFs must be completed by the designated study personnel. It is the responsibility of the principal investigator to ensure that accurate eCRFs are completed in a timely manner.

16.4 Source Document Maintenance

Source documents are defined as the results of original observations and activities of a clinical investigation. Source documents may include, but are not limited to, study progress notes, email correspondences, computer printouts, laboratory data, and recorded data from automated instruments. All source documents produced in this study will be maintained by the investigator(s) and made available for inspection by Sponsor representatives and/or regulatory authorities. The original signed informed consent form for each participating subject shall be filed with records kept by the investigator(s) and a copy given to the subject.

16.5 Study Monitoring Requirements Site visits will be conducted by the Sponsor or authorized Sponsor representatives to inspect study data, subject’s medical records, and CRFs in accordance with ICH guidelines, GCPs, and the respective U.S. or foreign regulations and guidelines, as applicable.

The investigator will permit representatives of the Sponsor and/or regulatory authorities the ability to inspect facilities and records relevant to this study.

16.6 Study Completion The Sponsor requires the following data and materials before a study can be considered complete or terminated:

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1. Laboratory findings, clinical data, and all special test results from screening through the end of the study follow-up period. 2. eCRFs properly completed by appropriate study personnel and signed and dated by the investigator. 3. Complete Drug Accountability records (drug inventory log and an inventory of returned or destroyed clinical material). 4. Copies of protocol amendments and IRB/IEC approval/notification, if appropriate.

17. PROTECTION OF HUMAN SUBJECTS AND GENERAL STUDY ADMINISTRATION This study will be conducted in compliance with the ICH E6 GCP (consolidated guidelines and the ethical principles of the Declaration of Helsinki), and any additional national or IRB/IEC- required procedures.

17.1 Informed Consent This study will be conducted in compliance with ICH E6 GCP (consolidated guidelines pertaining to informed consent). At the first visit, prior to initiation of any study-related procedures, subjects will give their written consent to participate in the study after having been informed about the nature and purpose of the study, participation/termination conditions, and risks and benefits; however microbiologic specimens collected during routine operative care prior to subject consent may be used for study purposes.

For subjects with diminished decision-making capacity and where applicable law permits, a Legally Authorized Representative (LAR) may consent on behalf of a prospective subject to the subject’s participation in the procedure(s) involved in this research study. Subjects should be re- consented in cases where their capacity to make decisions has returned.

In case of significant changes to safety, the subject will be re-consented. A copy of the signed consent document or a second original must be given to the representative/ proxy consenter. The original signed consent document will be retained by the investigator. Local legal requirements must be observed and informed consent must be sought from the subject as soon as possible afterwards, if feasible. This procedure must have prior agreement from the IEC/IRB. If applicable, the informed consent will be provided in a certified translation for non-English speaking subjects. Signed consent forms must remain in the subject’s study file and be available for verification by Sponsor personnel or regulatory agency at any time.

17.2 IRB/IEC Approval This protocol, the informed consent document, and all relevant supporting data must be submitted to the IRB/IEC for approval. IRB/IEC approval of the protocol, informed consent

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document, and any advertisement used to recruit study subjects must be obtained before the study may be initiated.

17.3 Subject Data Protection Prior to any testing under this protocol, including screening tests and assessments, candidates must also provide all authorizations required by local law (eg, PHI authorization in North America).

The subject will not be identified by name in the eCRF or in any study reports, and these reports will be used for research purposes only. The Sponsor and designee(s) and various government health agencies may inspect the records of this study. Every effort will be made to keep the subject’s personal medical data confidential.

18. DATA MANAGEMENT AND MONITORING Training sessions, regular monitoring of investigators by sponsor-designated personnel, instruction manuals, data verification, cross-checking, and data audits will be performed to ensure quality of all study data. Investigator meetings will be performed to prepare investigators and other study personnel for appropriate collection of study data.

The Sponsor will perform internal and/or external audits of study data.

It will be the responsibility of the investigator(s) to assure that essential laboratory and pharmacy manuals are available at the investigator/institutional site. Any or all of these documents may be subject to, and should be available for, audit by the Sponsor’s auditor and/or inspection by regulatory authorities.

18.1 Direct Access to Source Data/Documents The investigator agrees by his/her participation that the results of this study may be used for submission to national and/or international registration and supervising authorities. If required, these authorities will be provided with the names of investigators, their addresses, qualifications, and extent of involvement. It is understood that the investigator is required to provide the Sponsor with all study data, complete reports, and access to all study records.

Data generated by this study must be available for inspection by any regulatory authorities, by the Sponsor, and the IRB/IEC as appropriate. At a subject’s request, medical information may be given to his or her personal physician or other appropriate medical personnel responsible for his or her welfare. Subject medical information obtained during the course of this study is confidential and disclosure to third parties other than those noted above is prohibited.

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18.2 Retention of Records U.S. Investigational New Drug (IND) exemption regulations require that records and documents pertaining to the conduct of this study and the distribution of investigational drugs including CRFs, consent forms, laboratory test results, and medication inventory records must be kept on file by the principal investigator for a minimum of two years after notification by the Sponsor that a marketing application has been approved for eravacycline [Code of Federal Regulations, Title 21, Part 312, Section 62(c)]. If no application is filed or approved, these records must be kept for two years after the investigation has been discontinued and the U.S. FDA and applicable foreign authorities have been notified. The Sponsor will notify the investigator of these events. No study records should be destroyed without prior authorization from the Sponsor. This study will be conducted under a U.S. IND; for study sites outside the United States, the investigator must comply with U.S. FDA IND regulations and with those of the relevant national and local regulatory authorities.

19. FINANCING AND INSURANCE The financing and insurance for this study are outlined in the Clinical Trial Agreement and must comply with all local and national rules and regulations.

20. PUBLICATION POLICY The publication policy is outlined in the Clinical Trial Agreement. The data generated in this clinical trial are the exclusive property of Tetraphase Pharmaceuticals Inc. and are confidential. Written approval from Tetraphase is required prior to disclosing any information related to this clinical trial.

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21. REFERENCES 1. Solomkin, J.S., et al., Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis, 2010. 50(2): p. 133-64. 2. Paterson, D.L., et al., In vitro susceptibilities of aerobic and facultative Gram-negative bacilli isolated from patients with intra-abdominal infections worldwide: the 2003 Study for Monitoring Antimicrobial Resistance Trends (SMART). J Antimicrob Chemother, 2005. 55(6): p. 965-73. 3. Goldstein, E.J. and D.R. Snydman, Intra-abdominal infections: review of the bacteriology, antimicrobial susceptibility and the role of ertapenem in their therapy. J Antimicrob Chemother, 2004. 53 Suppl 2: p. ii29-36. 4. Snydman, D.R., et al., National survey on the susceptibility of Bacteroides fragilis group: report and analysis of trends in the United States from 1997 to 2004. Antimicrob Agents Chemother, 2007. 51(5): p. 1649-55. 5. A Phase 2, Randomized, Double-Blind, Double-Dummy, Multicenter, Prospective Study to Assess the Efficacy, Safety, and Pharmacokinetics of 2 Dose Regimens of TP 434 Compared with Ertapenem in Adult Community-Acquired Complicated Intra-abdominal Infections. Clinical Study Report TP-434-P2-cIAI-1, Oct. 4, 2012, Tetraphase Pharmaceuticals, Inc. Watertown, MA. 6. Brown, R. and B. Bhyravbhatla, Computational analysis of eravacycline binding to the ribosome A-site. Xtal Biostructures, Natick, MA. July 24, 2008. 7. Chopra, I., Glycylcyclines: third-generation tetracycline antibiotics. Curr Opin Pharmacol, 2001. 1(5): p. 464-9. 8. Roberts, M.C., Update on acquired tetracycline resistance genes. FEMS Microbiol Lett, 2005. 245(2): p. 195-203.

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APPENDIX 1: APACHE II SCORE High Abnormal Range Normal Low Abnormal Range Acute Physiology Score (APS) Points +4 +3 +2 +1 0 +1 +2 +3 +4 1. Temperature rectal or tympanic (°C) •41 39-40.9 38.5-38.9 36.0-38.4 34-35.9 32-33.9 30-31.9 ”29.9 Add 0.5°C if oral 2. Mean arterial pressure (mmHg) •160 130-159 110-129 70-109 50-69 ”49 3. Heart rate (ventricular response) •180 140-179 110-139 70-109 55-69 40-54 ”39 4. Respiratory rate (non-ventilated or •50 35-49 25-34 12-24 10-11 6-9 <5 ventilated) 5. Oxygenation:AaDO or PaO (mmHg) 2 2 •500 350-499 200-349 <200 i. if FiO2>0.5, record AaDO2 ii. if FiO2<0.5, record PaO2 >70 61-70 55-60 <55 6. Arterial pH •7.7 7.6-7.69 7.5-7.59 7.33-7.49 7.25-7.32 7.15-7.24 <7.15 If no ABGs record Serum HCO3 below Not preferred, use ONLY if no ABGs <52 41-51.9 32-40.9 22-31.9 18-21.9 15-17.9 <15 Serum HCO3 (venous-mMol/L) 7. Serum Sodium (mMol/L) •180 160-179 155-159 150-154 130-149 120-129 111-119 ”110 8. Serum Potassium (mMol/L) •7 6-6.9 5.5-5.9 3.5-5.4 3-3.4 2.5-2.9 <2.5 9. Serum Creatinine (mg/dL) •3.5 2-3.4 1.5-1.9 0.6-1.4 <0.6 Double points for acute renal failure 10. Hematocrit (%) •60 50-59.9 46-49.9 30-45.9 20-29.9 <20 11. White Blood Count (k/mm3) •40 20-39.9 15-19.9 3-14.9 1-2.9 <1 12. Glasgow Coma Scale (see below) 15 – GCS = (Score = 15 minus actual GCS) Total APS Points Sum of the 12 individual variable points A

Glasgow Coma Scale (Circle Appropriate Responses) Chronic Health Evaluation (CHE) Eyes open Verbal - nonintubated If “yes” give +5 for non-operative or emergency postoperative subjects 4 - spontaneously 5 - oriented and give +2 if elective postoperative subjects 3 - to speech 4 - confused Liver

2 - to pain 3 - inappropriate words Cirrhosis with PHT or encephalopathy 1 - no response 2 - incomprehensible sounds Cardiovascular Age Points APACHE II Score 1 - no response Class IV angina or at rest or with minimal self-care activities Age Points (A + B +C) Pulmonary Motor response Verbal - intubated ”44 0 APS Points 45-54 2 Chronic hypoxemia or hypercapnia or polycytaemia of PHT > 40 mmHg A 6 - to verbal command 5 - seems able to talk Kidney 5 - localizes to pain 3 - questionable ability to talk 55-64 3 Age Points B 65-74 5 Chronic peritoneal or hemodialysis 4 - withdraws to pain 1 - generally unresponsive Immune System •75 6 CHE Points C 3 - flexion to pain Immune compromised host 2 - extension to pain Total Age Total APACHE 1 - no response Points B Total CHE Points C II Score

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APPENDIX 2: CENTRAL SAFETY LABORATORY TESTS

Hematology: Hemoglobin Neutrophils Hematocrit Lymphocytes Erythrocyte count (RBC) Monocytes Mean cell volume (MCV) Eosinophils Mean cell hemoglobin (MCH) Basophils Mean cell hemoglobin concentration (MCHC) Platelets Leukocyte count (WBC)

Coagulation: Prothrombin time Partial thromboplastin time

Urinalysis: (May be semi-quantitative if standard at respective hospital laboratory) pH Ketones Protein Bilirubin Glucose Urobilinogen Urine microscopy (RBC, WBC, crystals, and casts)

Clinical Chemistry: Magnesium Lactic dehydrogenase (LDH) Bicarbonate Total and indirect bilirubin Sodium Total cholesterol Potassium Glucose, non-fasting Phosphorus Total protein Chloride Albumin Calcium Creatinine Alkaline phosphatase Urea nitrogen Gamma-glutamyl transferase (GGT) Uric acid Alanine aminotransferase (ALT/GPT) Amylase Aspartate aminotransferase (AST/GOT) Lipase Creatine kinase (CK) Serum pregnancy test (women of childbearing potential only) NOTE: If a serum pregnancy test is not available at the investigator site then a urine pregnancy test may be utilized locally.

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APPENDIX 3: BLOOD PK SAMPLE COLLECTION, HANDLING, PREPARATION AND SHIPPING

The timelines and procedures for PK sampling, handling, dispatch, and analysis are detailed in the Central Laboratory Manual.

Day 1 (Dose Cycle 1) - PK Sampling Schedule PK Timea Sample Number 30 – 0 min prior to the start of Dose 1, Bag 1 1 End of infusion of Dose 1, Bag 1 ± 2 min 2 +3-h post the start of Dose 1, Bag 1 3 +7-h post the start of Dose 1, Bag 1 4 30 – 0 min prior to thes start of Dose 2, Bag 1 5 a PK sample must be collected within ± 10 minutes of target time.

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Downloaded From: https://jamanetwork.com/ on 09/27/2021 6.2 Post-Marketing Experience 12.3 Pharmacokinetics 2FWREHU 6.3 Adverse Laboratory Changes in Clinical Trials 12.4 Microbiology 7 DRUG INTERACTIONS 13 NONCLINICAL TOXICOLOGY HIGHLIGHTS OF PRESCRIBING INFORMATION x Due to the use of lidocaine HCl as a diluent, INVANZ administered 7.1 Probenecid 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility These highlights do not include all the information needed to use intramuscularly is contraindicated in patients with a known 7.2 Valproic Acid 13.2 Animal Toxicology and/or Pharmacology INVANZ safely and effectively. See full prescribing information for hypersensitivity to local anesthetics of the amide type. (4) 8 USE IN SPECIFIC POPULATIONS 14 CLINICAL STUDIES INVANZ. 8.1 Pregnancy 14.1 Adults ------WARNINGS AND PRECAUTIONS ------8.2 Labor and Delivery 14.2 Pediatric Patients ® INVANZ (ertapenem for injection) for intravenous (IV) or x Serious hypersensitivity (anaphylactic) reactions have been 8.3 Nursing Mothers 15 REFERENCES intramuscular (IM) use reported in patients receiving ȕ-lactams. (5.1) 8.4 Pediatric Use 16 HOW SUPPLIED/STORAGE AND HANDLING Initial U.S. Approval: 2001 x Seizures and other central nervous system adverse experiences 8.5 Geriatric Use 16.1 How Supplied have been reported during treatment. (5.2) 8.6 Patients with Renal Impairment 16.2 Storage and Handling To reduce the development of drug-resistant bacteria and maintain the x Co-administration of INVANZ with valproic acid or divalproex 8.7 Patients with Hepatic Impairment 17 PATIENT COUNSELING INFORMATION effectiveness of INVANZ and other antibacterial drugs, INVANZ should sodium reduces the serum concentration of valproic acid 10 OVERDOSAGE 17.1 Instructions for Patients be used only to treat or prevent infections that are proven or strongly potentially increasing the risk of breakthrough seizures. (5.3) 11 DESCRIPTION suspected to be caused by susceptible bacteria. x Clostridium difficile-associated diarrhea (ranging from mild diarrhea 12 CLINICAL PHARMACOLOGY *Sections or subsections omitted from the full prescribing information to fatal colitis): Evaluate if diarrhea occurs. (5.4) 12.1 Mechanism of Action are not listed. ------INDICATIONS AND USAGE ------x Caution should be taken when administering INVANZ INVANZ is a penem antibacterial indicated in adult patients and intramuscularly to avoid inadvertent injection into a blood vessel. pediatric patients (3 months of age and older) for the treatment of the (5.5) following moderate to severe infections caused by susceptible bacteria: FULL PRESCRIBING INFORMATION x Complicated intra-abdominal infections. (1.1) ------ADVERSE REACTIONS------x Complicated skin and skin structure infections, including diabetic Adults: foot infections without osteomyelitis. (1.2) The most common adverse reactions (•5%) in patients treated with 1 INDICATIONS AND USAGE x Community-acquired pneumonia. (1.3) INVANZ, including those who were switched to therapy with an oral ® x Complicated urinary tract infections including pyelonephritis. (1.4) antimicrobial, were diarrhea, nausea, headache and infused vein To reduce the development of drug-resistant bacteria and maintain the effectiveness of INVANZ and complication. (6.1) x Acute pelvic infections including postpartum endomyometritis, In the prophylaxis indication the overall adverse experience profile was other antibacterial drugs, INVANZ should be used only to treat or prevent infections that are proven or septic abortion and post surgical gynecologic infections. (1.5) generally comparable to that observed for ertapenem in other clinical strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are INVANZ is indicated in adults for the prophylaxis of surgical site trials. (6.1) infection following elective colorectal surgery. (1.6) available, they should be considered in selecting or modifying antibacterial therapy. In the absence of Pediatrics: such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of ------DOSAGE AND ADMINISTRATION ------Adverse reactions in this population were comparable to adults. The therapy. Do not mix or co-infuse INVANZ with other medications. Do not most common adverse reactions (•5%) in pediatric patients treated use diluents containing dextrose (D–D–glucose). (2.1) with INVANZ, including those who were switched to therapy with an INVANZ should be infused over 30 minutes in both the Treatment and oral antimicrobial, were diarrhea, vomiting and infusion site pain. (6.1) Treatment Prophylactic regimens. (2.1) INVANZ is indicated for the treatment of adult patients and pediatric patients (3 months of age and Dosing considerations should be made in adults with advanced or end- To report SUSPECTED ADVERSE REACTIONS, contact Merck older) with the following moderate to severe infections caused by susceptible isolates of the designated stage renal impairment and those on hemodialysis. (2.4, 2.5) Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877- Treatment regimen: 888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. microorganisms [see Dosage and Administration (2)]. x Adults and pediatric patients 13 years of age and older. The 1.1 Complicated Intra-Abdominal Infections ------DRUG INTERACTIONS ------dosage should be 1 gram once a day intravenously or x Co-administration with probenecid inhibits the renal excretion of INVANZ is indicated for the treatment of complicated intra-abdominal infections due to Escherichia intramuscularly. (2.2) ertapenem and is therefore not recommended. (7.1) coli, Clostridium clostridioforme, Eubacterium lentum, Peptostreptococcus species, Bacteroides fragilis, x Patients 3 months to 12 years of age should be administered x The concomitant use of ertapenem and valproic acid/divalproex 15 mg/kg twice daily (not to exceed 1 g/day intravenously or Bacteroides distasonis, Bacteroides ovatus, Bacteroides thetaiotaomicron, or Bacteroides uniformis. sodium is generally not recommended. Anti-bacterials other than intramuscularly.) (2.2) 1.2 Complicated Skin and Skin Structure Infections, Including Diabetic Foot Infections without carbapenems should be considered to treat infections in patients x Intravenous infusion may be administered in adults and pediatrics whose seizures are well controlled on valproic acid or divalproex Osteomyelitis for up to 14 days or intramuscular injection for up to 7 days. (2.1) sodium. (5.2, 7.2) INVANZ is indicated for the treatment of complicated skin and skin structure infections, including Prophylaxis regimen for adults: diabetic foot infections without osteomyelitis due to Staphylococcus aureus (methicillin susceptible x 1 gram single dose given 1 hour prior to elective colorectal ------USE IN SPECIFIC POPULATIONS ------surgery. (2.3) x Renal Impairment: Dose adjustment is necessary, if creatinine isolates only), Streptococcus agalactiae, Streptococcus pyogenes, Escherichia coli, Klebsiella 2 3$&.$*(,16(57 clearance is ”30 mL/min/1.73 m . (2.4, 8.6, 12.3) pneumoniae, Proteus mirabilis, Bacteroides fragilis, Peptostreptococcus species, Porphyromonas ------DOSAGE FORMS AND STRENGTHS ------

Š asaccharolytica, or Prevotella bivia. INVANZ has not been studied in diabetic foot infections with x Vial 1 gram. (3) See 17 for PATIENT COUNSELING INFORMATION x ADD-Vantage® vial: 1 gram. (3) concomitant osteomyelitis [see Clinical Studies (14)]. Revised: 06/2013 1.3 Community Acquired Pneumonia ------CONTRAINDICATIONS ------INVANZ is indicated for the treatment of community acquired pneumonia due to Streptococcus x Known hypersensitivity to product components or anaphylactic reactions to ȕ-lactams. (4) pneumoniae (penicillin susceptible isolates only) including cases with concurrent bacteremia, Haemophilus influenzae (beta-lactamase negative isolates only), or Moraxella catarrhalis. 1.4 Complicated Urinary Tract Infections Including Pyelonephritis FULL PRESCRIBING INFORMATION: CONTENTS* 2.4 Patients with Renal Impairment INVANZ is indicated for the treatment of complicated urinary tract infections including pyelonephritis 1 INDICATIONS AND USAGE 2.5 Patients on Hemodialysis due to Escherichia coli, including cases with concurrent bacteremia, or Klebsiella pneumoniae. 1.1 Complicated Intra-Abdominal Infections 2.6 Patients with Hepatic Impairment 1.5 Acute Pelvic Infections Including Postpartum Endomyometritis, Septic Abortion and Post 1.2 Complicated Skin and Skin Structure Infections, Including 2.7 Preparation and Reconstitution for Administration Surgical Gynecologic Infections Diabetic Foot Infections without Osteomyelitis 3 DOSAGE FORMS AND STRENGTHS 1.3 Community Acquired Pneumonia 4 CONTRAINDICATIONS INVANZ is indicated for the treatment of acute pelvic infections including postpartum endomyometritis, 1.4 Complicated Urinary Tract Infections Including Pyelonephritis 5 WARNINGS AND PRECAUTIONS septic abortion and post surgical gynecological infections due to Streptococcus agalactiae, Escherichia 1.5 Acute Pelvic Infections Including Postpartum 5.1 Hypersensitivity Reactions coli, Bacteroides fragilis, Porphyromonas asaccharolytica, Peptostreptococcus species, or Prevotella Endomyometritis, Septic Abortion and Post Surgical 5.2 Seizure Potential bivia. Gynecologic Infections 5.3 Interaction with Valproic Acid 1.6 Prophylaxis of Surgical Site Infection Following Elective 5.4 Clostridium difficile-Associated Diarrhea (CDAD) Colorectal Surgery 5.5 Caution with Intramuscular Administration Prevention 2 DOSAGE AND ADMINISTRATION 5.6 Development of Drug-Resistant Bacteria INVANZ is indicated in adults for: 2.1 Instructions for Use in All Patients 5.7 Laboratory Tests 2.2 Treatment Regimen 6 ADVERSE REACTIONS

2.3 Prophylactic Regimen in Adults 6.1 Clinical Trials Experience 2

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1.6 Prophylaxis of Surgical Site Infection Following Elective Colorectal Surgery Table 2 INVANZ is indicated for the prevention of surgical site infection following elective colorectal surgery. Prophylaxis Guidelines for Adults Daily Dose Recommended Duration 2 DOSAGE AND ADMINISTRATION Indication (IV) of Total Antimicrobial Adults Treatment 2.1 Instructions for Use in All Patients For Intravenous or Intramuscular Use Prophylaxis of surgical site 1 g Single intravenous dose infection following elective given 1 hour prior to DO NOT MIX OR CO-INFUSE INVANZ WITH OTHER MEDICATIONS. DO NOT USE DILUENTS colorectal surgery surgical incision CONTAINING DEXTROSE (D-D-GLUCOSE). INVANZ may be administered by intravenous infusion for up to 14 days or intramuscular injection for up to 7 days. When administered intravenously, INVANZ should be infused over a period of 30 minutes. 2.4 Patients with Renal Impairment Intramuscular administration of INVANZ may be used as an alternative to intravenous administration in INVANZ may be used for the treatment of infections in adult patients with renal impairment. In patients the treatment of those infections for which intramuscular therapy is appropriate. whose creatinine clearance is !30 mL/min/1.73 m2, no dosage adjustment is necessary. Adult patients 2.2 Treatment Regimen with severe renal impairment (creatinine clearance d30 mL/min/1.73 m2) and end-stage renal disease 13 years of age and older (creatinine clearance d10 mL/min/1.73 m2) should receive 500 mg daily. A supplementary dose of 150 mg The dose of INVANZ in patients 13 years of age and older is 1 gram (g) given once a day [see Clinical is recommended if ertapenem is administered within 6 hours prior to hemodialysis. There are no data in Pharmacology (12.3)]. pediatric patients with renal impairment. 3 months to 12 years of age 2.5 Patients on Hemodialysis The dose of INVANZ in patients 3 months to 12 years of age is 15 mg/kg twice daily (not to exceed When adult patients on hemodialysis are given the recommended daily dose of 500 mg of INVANZ 1 g/day). within 6 hours prior to hemodialysis, a supplementary dose of 150 mg is recommended following the Table 1 presents treatment guidelines for INVANZ. hemodialysis session. If INVANZ is given at least 6 hours prior to hemodialysis, no supplementary dose is needed. There are no data in patients undergoing peritoneal dialysis or hemofiltration. There are no data Table 1 in pediatric patients on hemodialysis. Treatment Guidelines for Adults and Pediatric Patients With Normal Renal Function* and Body Weight 1 Daily Dose Daily Dose Recommended When only the serum creatinine is available, the following formula may be used to estimate creatinine Infection† (IV or IM) (IV or IM) Duration of Total clearance. The serum creatinine should represent a steady state of renal function. Adults and Pediatric Pediatric Patients 3 Antimicrobial (weight in kg) x (140-age in years) Patients 13 years of months to 12 years of Treatment Males: age and older age (72) x serum creatinine (mg/100 mL) Females: (0.85) x (value calculated for males) Complicated intra-abdominal 1 g 15 mg/kg 5 to 14 days infections twice daily‡ 2.6 Patients with Hepatic Impairment Complicated skin and skin structure 1 g 15 mg/kg 7 to 14 days¶ No dose adjustment recommendations can be made in patients with hepatic impairment [see Use in infections, including diabetic foot twice daily‡ § Specific Populations (8.7) and Clinical Pharmacology (12.3)]. infections 2.7 Preparation and Reconstitution for Administration Community acquired pneumonia 1 g 15 mg/kg 10 to 14 days# Vials twice daily‡ Adults and pediatric patients 13 years of age and older Preparation for intravenous administration: Complicated urinary tract 1 g 15 mg/kg 10 to 14 days# infections, including pyelonephritis twice daily‡ DO NOT MIX OR CO-INFUSE INVANZ WITH OTHER MEDICATIONS. DO NOT USE DILUENTS CONTAINING DEXTROSE (D-D-GLUCOSE). Acute pelvic infections including 1 g 15 mg/kg 3 to 10 days ‡ INVANZ MUST BE RECONSTITUTED AND THEN DILUTED PRIOR TO ADMINISTRATION. postpartum endomyometritis, septic twice daily 1. Reconstitute the contents of a 1 g vial of INVANZ with 10 mL of one of the following: Water for abortion and post surgical gynecologic infections Injection, 0.9% Sodium Chloride Injection or Bacteriostatic Water for Injection. 2. Shake well to dissolve and immediately transfer contents of the reconstituted vial to 50 mL of * defined as creatinine clearance !90 mL/min/1.73 m2 0.9% Sodium Chloride Injection. † due to the designated pathogens [see Indications and Usage (1)] 3. Complete the infusion within 6 hours of reconstitution. ‡ not to exceed 1 g/day § Preparation for intramuscular administration: INVANZ has not been studied in diabetic foot infections with concomitant osteomyelitis [see Clinical Studies INVANZ MUST BE RECONSTITUTED PRIOR TO ADMINISTRATION. (14.1)]. 2 ¶ adult patients with diabetic foot infections received up to 28 days of treatment (parenteral or parenteral plus 1. Reconstitute the contents of a 1 g vial of INVANZ with 3.2 mL of 1.0% lidocaine HCl injection oral switch therapy) (without epinephrine). Shake vial thoroughly to form solution. # duration includes a possible switch to an appropriate oral therapy, after at least 3 days of parenteral therapy, 2. Immediately withdraw the contents of the vial and administer by deep intramuscular injection into once clinical improvement has been demonstrated. a large muscle mass (such as the gluteal muscles or lateral part of the thigh).

2.3 Prophylactic Regimen in Adults

Table 2 presents prophylaxis guidelines for INVANZ. 1 Cockcroft and Gault equation: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976 2 Refer to the prescribing information for lidocaine HCl.

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3. The reconstituted IM solution should be used within 1 hour after preparation. NOTE: THE RECONSTITUTED SOLUTION SHOULD NOT BE ADMINISTERED INTRAVENOUSLY. Pediatric patients 3 months to 12 years of age Preparation for intravenous administration: DO NOT MIX OR CO-INFUSE INVANZ WITH OTHER MEDICATIONS. DO NOT USE DILUENTS CONTAINING DEXTROSE (D-D-GLUCOSE). INVANZ MUST BE RECONSTITUTED AND THEN DILUTED PRIOR TO ADMINISTRATION. 1. Reconstitute the contents of a 1 g vial of INVANZ with 10 mL of one of the following: Water for Injection, 0.9% Sodium Chloride Injection or Bacteriostatic Water for Injection. 2. Shake well to dissolve and immediately withdraw a volume equal to 15 mg/kg of body weight (not to exceed 1 g/day) and dilute in 0.9% Sodium Chloride Injection to a final concentration of 20 mg/mL or less. 3. Complete the infusion within 6 hours of reconstitution. Preparation for intramuscular administration: INVANZ MUST BE RECONSTITUTED PRIOR TO ADMINISTRATION. 1. Reconstitute the contents of a 1 g vial of INVANZ with 3.2 mL of 1.0% lidocaine HCl injection (without epinephrine). Shake vial thoroughly to form solution. 2. Immediately withdraw a volume equal to 15 mg/kg of body weight (not to exceed 1 g/day) and administer by deep intramuscular injection into a large muscle mass (such as the gluteal muscles or lateral part of the thigh). 3. The reconstituted IM solution should be used within 1 hour after preparation. NOTE: THE RECONSTITUTED SOLUTION SHOULD NOT BE ADMINISTERED INTRAVENOUSLY. To remove the vial port cover, grasp the tab on the pull ring, pull up to break the three tie strings, then ADD-Vantage®3 Vials pull back to remove the cover. (SEE FIGURE 3.) INVANZ in ADD-Vantage® vials should be reconstituted with ADD-Vantage® diluent containers Screw the vial into the vial port until it will go no further. THE VIAL MUST BE SCREWED IN TIGHTLY containing 50 mL or 100 mL of 0.9% Sodium Chloride Injection. TO ASSURE A SEAL. This occurs approximately ½ turn (180°) after the first audible click. (SEE FIGURE 4.) The clicking sound does not assure a seal; the vial must be turned as far as it will go. NOTE: Once INSTRUCTIONS FOR USE OF vial is seated, do not attempt to remove. (SEE FIGURE 4.) INVANZ® Recheck the vial to assure that it is tight by trying to turn it further in the direction of assembly. (Ertapenem for Injection) Label appropriately. IN ADD-Vantage VIALS

For I.V. Use Only.

To Open Diluent Container: Peel overwrap from the corner and remove container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually.

To Assemble Vial and Flexible Diluent Container: (Use Aseptic Technique) Remove the protective covers from the top of the vial and the vial port on the diluent container as follows: To remove the breakaway vial cap, swing the pull ring over the top of the vial and pull down far enough to start the opening. (SEE FIGURE 1.) Pull the ring approximately half way around the cap and then pull straight up to remove the cap. (SEE FIGURE 2.) NOTE: DO NOT ACCESS VIAL WITH SYRINGE.

To Prepare Admixture: Squeeze the bottom of the diluent container gently to inflate the portion of the container surrounding 3 Registered trademark of Hospira Laboratories, Inc. the end of the drug vial.

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With the other hand, push the drug vial down into the container telescoping the walls of the container. 3 DOSAGE FORMS AND STRENGTHS Grasp the inner cap of the vial through the walls of the container. (SEE FIGURE 5.) Vials Pull the inner cap from the drug vial. (SEE FIGURE 6.) Verify that the rubber stopper has been pulled INVANZ is a sterile lyophilized powder in a vial containing 1.046 g ertapenem sodium equivalent to 1 g out, allowing the drug and diluent to mix. ertapenem for intravenous infusion or for intramuscular injection. Mix container contents thoroughly and use within the specified time. ADD-Vantage® Vials INVANZ is a lyophilized powder in an ADD-Vantage® vial containing 1.046 g ertapenem sodium equivalent to 1 g ertapenem for intravenous infusion.

4 CONTRAINDICATIONS x INVANZ is contraindicated in patients with known hypersensitivity to any component of this product or to other drugs in the same class or in patients who have demonstrated anaphylactic reactions to beta-lactams. x Due to the use of lidocaine HCl as a diluent, INVANZ administered intramuscularly is contraindicated in patients with a known hypersensitivity to local anesthetics of the amide type.

5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with beta-lactams. These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe hypersensitivity reactions when treated with another beta- lactam. Before initiating therapy with INVANZ, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, other beta-lactams and other allergens. If an Preparation for Administration: allergic reaction to INVANZ occurs, discontinue the drug immediately. Serious anaphylactic reactions (Use Aseptic Technique) require immediate emergency treatment as clinically indicated. Confirm the activation and admixture of vial contents. 5.2 Seizure Potential Check for leaks by squeezing container firmly. If leaks are found, discard unit as sterility may be Seizures and other central nervous system (CNS) adverse experiences have been reported during impaired. treatment with INVANZ [see Adverse Reactions (6.1)]. During clinical investigations in adult patients Close flow control clamp of administration set. treated with INVANZ (1 g once a day), seizures, irrespective of drug relationship, occurred in 0.5% of Remove cover from outlet port at bottom of container. patients during study therapy plus 14-day follow-up period [see Adverse Reactions (6.1)]. These Insert piercing pin of administration set into port with a twisting motion until the pin is firmly seated. experiences have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history NOTE: See full directions on administration set carton. of seizures) and/or compromised renal function. Close adherence to the recommended dosage regimen Lift the free end of the hanger loop on the bottom of the vial, breaking the two tie strings. Bend the is urged, especially in patients with known factors that predispose to convulsive activity. Anticonvulsant loop outward to lock it in the upright position, then suspend container from hanger. therapy should be continued in patients with known seizure disorders. If focal tremors, myoclonus, or Squeeze and release drip chamber to establish proper fluid level in chamber. seizures occur, patients should be evaluated neurologically, placed on anticonvulsant therapy if not Open flow control clamp and clear air from set. Close clamp. already instituted, and the dosage of INVANZ re-examined to determine whether it should be decreased Attach set to venipuncture device. If device is not indwelling, prime and make venipuncture. or discontinued. Regulate rate of administration with flow control clamp. 5.3 Interaction with Valproic Acid WARNING: Do not use flexible container in series connections. Case reports in the literature have shown that co-administration of carbapenems, including ertapenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid Storage concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this INVANZ (Ertapenem for Injection) 1 g single dose ADD-Vantage® vials should be prepared with ® interaction, therefore increasing the risk of breakthrough seizures. Increasing the dose of valproic acid or ADD-Vantage diluent containers containing 50 mL or 100 mL of 0.9% Sodium Chloride Injection. When divalproex sodium may not be sufficient to overcome this interaction. The concomitant use of ertapenem prepared with this diluent, INVANZ (Ertapenem for Injection) maintains satisfactory potency for 6 hours and valproic acid/divalproex sodium is generally not recommended. Anti-bacterials other than at room temperature (25°C) or for 24 hours under refrigeration (5°C) and used within 4 hours after carbapenems should be considered to treat infections in patients whose seizures are well controlled on removal from refrigeration. Solutions of INVANZ should not be frozen. valproic acid or divalproex sodium. If administration of INVANZ is necessary, supplemental anti- Before administering, see accompanying package circular for INVANZ (Ertapenem for Injection). convulsant therapy should be considered [see Drug Interactions (7.2)]. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to 5.4 Clostridium difficile-Associated Diarrhea (CDAD) use, whenever solution and container permit. Solutions of INVANZ range from colorless to pale yellow. CDAD has been reported with use of nearly all antibacterial agents, including ertapenem, and may Variations of color within this range do not affect the potency of the product. range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of Clostridium difficile. Clostridium difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of Clostridium difficile cause increased morbidity and mortality, as these

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infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be Adverse Events (N=802) (N=1152) (N=942) considered in all patients who present with diarrhea following antibiotic use. Careful medical history is Local: necessary since CDAD has been reported to occur over two months after the administration of Infused vein complication 7.1 7.9 5.4 6.7 Systemic: antibacterial agents. Death 2.5 1.6 1.3 1.6 If CDAD is suspected or confirmed, ongoing antibiotic use not directed against Clostridium difficile Edema/swelling 3.4 2.5 2.9 3.3 may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, Fever 5.0 6.6 2.3 3.4 antibiotic treatment of Clostridium difficile, and surgical evaluation should be instituted as clinically Abdominal pain 3.6 4.8 4.3 3.9 Hypotension 2.0 1.4 1.0 1.2 indicated. Constipation 4.0 5.4 3.3 3.1 5.5 Caution with Intramuscular Administration Diarrhea 10.3 12.1 9.2 9.8 Caution should be taken when administering INVANZ intramuscularly to avoid inadvertent injection Nausea 8.5 8.7 6.4 7.4 Vomiting 3.7 5.3 4.0 4.0 into a blood vessel [see Dosage and Administration (2.7)]. ‡ Altered mental status 5.1 3.4 3.3 2.5 5.6 Development of Drug-Resistant Bacteria Dizziness 2.1 3.0 1.5 2.1 As with other antibiotics, prolonged use of INVANZ may result in overgrowth of non-susceptible Headache 5.6 5.4 6.8 6.9 organisms. Repeated evaluation of the patient's condition is essential. If superinfection occurs during Insomnia 3.2 5.2 3.0 4.1 Dyspnea 2.6 1.8 1.0 2.4 therapy, appropriate measures should be taken. Pruritus 2.0 2.6 1.0 1.9 Prescribing INVANZ in the absence of a proven or strongly suspected bacterial infection or a Rash 2.5 3.1 2.3 1.5 prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the Vaginitis 1.4 1.0 3.3 3.7 development of drug-resistant bacteria. * Includes Phase IIb/III Complicated intra-abdominal infections, Complicated skin and skin structure infections and Acute pelvic infections trials 5.7 Laboratory Tests † Includes Phase IIb/III Community acquired pneumonia and Complicated urinary tract infections, and Phase IIa trials While INVANZ possesses toxicity similar to the beta-lactam group of antibiotics, periodic assessment ‡ Includes agitation, confusion, disorientation, decreased mental acuity, changed mental status, somnolence, stupor of organ system function, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy. In patients treated for complicated intra-abdominal infections, death occurred in 4.7% (15/316) of patients receiving INVANZ and 2.6% (8/307) of patients receiving comparator drug. These deaths 6 ADVERSE REACTIONS occurred in patients with significant co-morbidity and/or severe baseline infections. Deaths were The following are described in greater detail in the Warnings and Precautions section. considered unrelated to study drugs by investigators. x Hypersensitivity Reactions [see Warnings and Precautions (5.1)] In clinical trials, seizure was reported during study therapy plus 14-day follow-up period in 0.5% of patients treated with INVANZ, 0.3% of patients treated with piperacillin/tazobactam and 0% of patients x Seizure Potential [see Warnings and Precautions (5.2)] treated with ceftriaxone [see Warnings and Precautions (5.2)]. x Interaction with Valproic Acid [see Warnings and Precautions (5.3)] Additional adverse experiences that were reported with INVANZ with an incidence !0.1% within each x Clostridium difficile-Associated Diarrhea (CDAD) [see Warnings and Precautions (5.4)] body system are listed below x Caution with Intramuscular Administration [see Warnings and Precautions (5.5)] Body as a Whole: abdominal distention, pain, chills, septicemia, septic shock, dehydration, gout, x Development of Drug-Resistant Bacteria [see Warnings and Precautions (5.6)] malaise, asthenia/fatigue, necrosis, candidiasis, weight loss, facial edema, injection site induration, x Laboratory Tests [see Warnings and Precautions (5.7)] injection site pain, extravasation, phlebitis/thrombophlebitis, flank pain, syncope Cardiovascular System: heart failure, hematoma, chest pain, hypertension, tachycardia, cardiac 6.1 Clinical Trials Experience arrest, bradycardia, arrhythmia, atrial fibrillation, heart murmur, ventricular tachycardia, asystole, subdural Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed hemorrhage in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and Digestive System: acid regurgitation, oral candidiasis, dyspepsia, gastrointestinal hemorrhage, may not reflect the rates observed in practice. anorexia, flatulence, C. difficile-associated diarrhea, stomatitis, dysphagia, hemorrhoids, ileus, Adults Receiving INVANZ as a Treatment Regimen cholelithiasis, duodenitis, esophagitis, gastritis, jaundice, mouth ulcer, pancreatitis, pyloric stenosis Clinical trials enrolled 1954 patients treated with INVANZ; in some of the clinical trials, parenteral Musculoskeletal System: leg pain therapy was followed by a switch to an appropriate oral antimicrobial [see Clinical Studies (14)]. Most Nervous System & Psychiatric: anxiety, nervousness, seizure [see Warnings and Precautions (5.2)], adverse experiences reported in these clinical trials were described as mild to moderate in severity. tremor, depression, hypesthesia, spasm, paresthesia, aggressive behavior, vertigo INVANZ was discontinued due to adverse experiences in 4.7% of patients. Table 3 shows the incidence Respiratory System: cough, pharyngitis, rales/rhonchi, respiratory distress, pleural effusion, of adverse experiences reported in t2.0% of patients in these trials. The most common drug-related hypoxemia, bronchoconstriction, pharyngeal discomfort, epistaxis, pleuritic pain, asthma, hemoptysis, adverse experiences in patients treated with INVANZ, including those who were switched to therapy with hiccups, voice disturbance an oral antimicrobial, were diarrhea (5.5%), infused vein complication (3.7%), nausea (3.1%), headache Skin & Skin Appendage: erythema, sweating, dermatitis, desquamation, flushing, urticaria (2.2%), and vaginitis in females (2.1%). Special Senses: taste perversion Urogenital System: renal impairment, oliguria/anuria, vaginal pruritus, hematuria, urinary retention, bladder dysfunction, vaginal candidiasis, vulvovaginitis. Table 3 In a clinical trial for the treatment of diabetic foot infections in which 289 adult diabetic patients were Incidence (%) of Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in t2.0% of Adult Patients Treated With INVANZ in Clinical Trials treated with INVANZ, the adverse experience profile was generally similar to that seen in previous clinical Piperacillin/ trials. INVANZ* Tazobactam* INVANZ† Ceftriaxone† Prophylaxis of Surgical Site Infection following Elective Colorectal Surgery 1 g daily 3.375 g q6h 1 g daily 1 or 2 g daily (N=774)

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In a clinical trial in adults for the prophylaxis of surgical site infection following elective colorectal Loose Stools 2.1 0.0 0.0 surgery in which 476 patients received a 1 g dose of INVANZ 1 hour prior to surgery and were then Vomiting 10.2 11.0 8.3 followed for safety 14 days post surgery, the overall adverse experience profile was generally comparable Pyrexia 4.9 6.0 8.3 to that observed for INVANZ in previous clinical trials. Table 4 shows the incidence of adverse Upper Respiratory Tract Infection 2.3 3.0 0.0 experiences other than those previously described above for INVANZ that were reported regardless of Headache 4.4 4.0 0.0 Cough 4.4 3.0 0.0 causality in t2.0% of patients in this trial. Diaper Dermatitis 4.7 4.0 0.0 Rash 2.9 2.0 8.3 Table 4 * Includes Phase IIb Complicated skin and skin structure infections, Community acquired pneumonia Incidence (%) of Adverse Experiences Reported During Study Therapy Plus and Complicated urinary tract infections trials in which patients 3 months to 12 years of age received 14-Day Follow-Up in t2.0% of Adult Patients Treated With INVANZ for INVANZ 15 mg/kg IV twice daily up to a maximum of 1 g or ceftriaxone 50 mg/kg/day IV in two divided Prophylaxis of Surgical Site Infections Following Elective Colorectal Surgery doses up to a maximum of 2 g, and patients 13 to 17 years of age received INVANZ 1 g IV daily or INVANZ Cefotetan ceftriaxone 50 mg/kg/day IV in a single daily dose. 2 g † 1 g Includes Phase IIb Acute pelvic infections and Complicated intra-abdominal infections trials in which (N = 476) Adverse Events (N = 476) patients 3 months to 12 years of age received INVANZ 15 mg/kg IV twice daily up to a maximum of 1 g Anemia 5.7 6.9 and patients 13 to 17 years of age received INVANZ 1 g IV daily or ticarcillin/clavulanate 50 mg/kg for Small intestinal obstruction 2.1 1.9 patients 60 kg or ticarcillin/clavulanate 3.0 g for patients !60 kg, 4 or 6 times a day. Pneumonia 2.1 4.0 Postoperative infection 2.3 4.0 Urinary tract infection 3.8 5.5 Additional adverse experiences that were reported with INVANZ with an incidence !0.5% within each Wound infection 6.5 12.4 Wound complication 2.9 2.3 body system are listed below: Atelectasis 3.4 1.9 Gastrointestinal Disorders: nausea General Disorders and Administration Site Condition: hypothermia, chest pain, upper abdominal Additional adverse experiences that were reported in this prophylaxis trial with INVANZ, regardless of pain; infusion site pruritus, induration, phlebitis, swelling, and warmth Infections and Infestations: candidiasis, oral candidiasis, viral pharyngitis, herpes simplex, ear causality, with an incidence !0.5% within each body system are listed below: infection, abdominal abscess Gastrointestinal Disorders: C. difficile infection or colitis, dry mouth, hematochezia Metabolism and Nutrition Disorders: decreased appetite General Disorders and Administration Site Condition: crepitations Musculoskeletal and Connective Tissue Disorders: arthralgia Infections and Infestations: cellulitis, abdominal abscess, fungal rash, pelvic abscess Nervous System Disorders: dizziness, somnolence Injury, Poisoning and Procedural Complications: incision site complication, incision site Psychiatric Disorders: insomnia hemorrhage, intestinal stoma complication, anastomotic leak, seroma, wound dehiscence, wound Reproductive System and Breast Disorders: genital rash secretion Respiratory, Thoracic and Mediastinal Disorders: wheezing, nasopharyngitis, pleural effusion, Musculoskeletal and Connective Tissue Disorders: muscle spasms rhinitis, rhinorrhea Nervous System Disorders: cerebrovascular accident Skin and Subcutaneous Tissue Disorders: dermatitis, pruritus, rash erythematous, skin lesion Renal and Urinary Disorders: dysuria, pollakiuria Vascular Disorders: phlebitis. Respiratory, Thoracic and Mediastinal Disorders: crackles lung, lung infiltration, pulmonary 6.2 Post-Marketing Experience congestion, pulmonary embolism, wheezing. The following additional adverse reactions have been identified during the post-approval use of Pediatric Patients Receiving INVANZ as a Treatment Regimen INVANZ. Because these reactions are reported voluntarily from a population of uncertain size, it is not Clinical trials enrolled 384 patients treated with INVANZ; in some of the clinical trials, parenteral always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. therapy was followed by a switch to an appropriate oral antimicrobial [see Clinical Studies (14)]. The Immune System Disorders: anaphylaxis including anaphylactoid reactions overall adverse experience profile in pediatric patients is comparable to that in adult patients. Table 5 Musculoskeletal and Connective Tissue Disorders: muscular weakness shows the incidence of adverse experiences reported in t2.0% of pediatric patients in clinical trials. The Nervous System Disorders: coordination abnormal, depressed level of consciousness, dyskinesia, most common drug-related adverse experiences in pediatric patients treated with INVANZ, including gait disturbance, myoclonus, tremor those who were switched to therapy with an oral antimicrobial, were diarrhea (6.5%), infusion site pain Psychiatric Disorders: altered mental status (including aggression, delirium), hallucinations (5.5%), infusion site erythema (2.6%), vomiting (2.1%). Skin and Subcutaneous Tissue Disorders: Drug Rash with Eosinophilia and Systemic Symptoms Table 5 (DRESS syndrome) Incidence (%) of Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in t2.0% of 6.3 Adverse Laboratory Changes in Clinical Trials Pediatric Patients Treated With INVANZ in Clinical Trials Ticarcillin/ Adults Receiving INVANZ as Treatment Regimen INVANZ*,† Ceftriaxone* Clavulanate† Laboratory adverse experiences that were reported during therapy in t2.0% of adult patients treated Adverse Events (N=384) (N=100) (N=24) with INVANZ in clinical trials are presented in Table 6. Drug-related laboratory adverse experiences that Local: were reported during therapy in t2.0% of adult patients treated with INVANZ, including those who were Infusion Site Erythema 3.9 3.0 8.3 switched to therapy with an oral antimicrobial, in clinical trials were ALT increased (6.0%), AST increased Infusion Site Pain 7.0 4.0 20.8 (5.2%), serum alkaline phosphatase increased (3.4%), and platelet count increased (2.8%). INVANZ was Systemic: discontinued due to laboratory adverse experiences in 0.3% of patients. Abdominal Pain 4.7 3.0 4.2 Constipation 2.3 0.0 0.0 Diarrhea 11.7 17.0 4.2

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Table 6 7 DRUG INTERACTIONS Incidence* (%) of Laboratory Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in t2.0% of Adult Patients Treated With INVANZ in Clinical Trials 7.1 Probenecid Piperacillin/ Probenecid interferes with the active tubular secretion of ertapenem, resulting in increased plasma ‡ ‡ § § INVANZ Tazobactam INVANZ Ceftriaxone concentrations of ertapenem [see Clinical Pharmacology (12.3)]. Co-administration of probenecid with 1 g daily 3.375 g q6h 1 g daily 1 or 2 g daily Adverse laboratory experiences (n†=766) (n†=755) (n†=1122) (n†=920) ertapenem is not recommended. ALT increased 8.8 7.3 8.3 6.9 7.2 Valproic Acid AST increased 8.4 8.3 7.1 6.5 Case reports in the literature have shown that co-administration of carbapenems, including Serum alkaline phosphatase increased 6.6 7.2 4.3 2.8 ertapenem, to patients receiving valproic acid or divalproex sodium results in a reduction of valproic acid Eosinophils increased 1.1 1.1 2.1 1.8 Hematocrit decreased 3.0 2.9 3.4 2.4 concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this Hemoglobin decreased 4.9 4.7 4.5 3.5 interaction, therefore increasing the risk of breakthrough seizures. Although the mechanism of this Platelet count increased 6.5 6.3 4.3 3.5 interaction is unknown, data from in vitro and animal studies suggest that carbapenems may inhibit the Urine RBCs increased 2.5 2.9 1.1 1.0 hydrolysis of valproic acid’s glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the Urine WBCs increased 2.5 3.2 1.6 1.1 * Number of patients with laboratory adverse experiences/Number of patients with the laboratory test serum concentrations of valproic acid [see Warnings and Precautions (5.3)]. † Number of patients with one or more laboratory tests ‡ Includes Phase IIb/III Complicated intra-abdominal infections, Complicated skin and skin structure infections and Acute 8 USE IN SPECIFIC POPULATIONS pelvic infections trials § Includes Phase IIb/III Community acquired pneumonia and Complicated urinary tract infections, and Phase IIa trials 8.1 Pregnancy Pregnancy Category B In mice and rats given intravenous doses of up to 700 mg/kg/day (for mice, approximately 3 times the Additional laboratory adverse experiences that were reported during therapy in !0.1% of patients recommended human dose of 1 g based on body surface area and for rats, approximately 1.2 times the treated with INVANZ in clinical trials include: increases in serum creatinine, serum glucose, BUN, total, human exposure at the recommended dose of 1 g based on plasma AUCs), there was no evidence of direct and indirect serum bilirubin, serum sodium and potassium, PT and PTT; decreases in serum developmental toxicity as assessed by external, visceral, and skeletal examination of the fetuses. potassium, serum albumin, WBC, platelet count, and segmented neutrophils. However, in mice given 700 mg/kg/day, slight decreases in average fetal weights and an associated In a clinical trial for the treatment of diabetic foot infections in which 289 adult diabetic patients were decrease in the average number of ossified sacrocaudal vertebrae were observed. Ertapenem crosses treated with INVANZ, the laboratory adverse experience profile was generally similar to that seen in the placental barrier in rats. previous clinical trials. There are, however, no adequate and well-controlled trials in pregnant women. Because animal Prophylaxis of Surgical Site Infection following Elective Colorectal Surgery reproduction studies are not always predictive of human response, this drug should be used during In a clinical trial in adults for the prophylaxis of surgical site infection following elective colorectal pregnancy only if clearly needed. surgery in which 476 patients received a 1 g dose of INVANZ 1 hour prior to surgery and were then 8.2 Labor and Delivery followed for safety 14 days post surgery, the overall laboratory adverse experience profile was generally INVANZ has not been studied for use during labor and delivery. comparable to that observed for INVANZ in previous clinical trials. 8.3 Nursing Mothers Pediatric Patients Receiving INVANZ as a Treatment Regimen Ertapenem is excreted in human breast milk [see Clinical Pharmacology (12.3)]. Caution should be Laboratory adverse experiences that were reported during therapy in t2.0% of pediatric patients exercised when INVANZ is administered to a nursing woman. INVANZ should be administered to nursing treated with INVANZ in clinical trials are presented in Table 7. Drug-related laboratory adverse mothers only when the expected benefit outweighs the risk. experiences that were reported during therapy in t2.0% of pediatric patients treated with INVANZ, 8.4 Pediatric Use including those who were switched to therapy with an oral antimicrobial, in clinical trials were neutrophil Safety and effectiveness of INVANZ in pediatric patients 3 months to 17 years of age are supported count decreased (3.0%), ALT increased (2.2%), and AST increased (2.1%). by evidence from adequate and well-controlled trials in adults, pharmacokinetic data in pediatric patients, and additional data from comparator-controlled trials in pediatric patients 3 months to 17 years of age Table 7 [see Indications and Usage (1.1), (1.2), (1.3), (1.4) and (1.5) and Clinical Studies (14.2)]. Incidence* (%) of Specific Laboratory Adverse Experiences Reported During Study Therapy INVANZ is not recommended in infants under 3 months of age as no data are available. Plus 14-Day Follow-Up in t2.0% of Pediatric Patients Treated With INVANZ in Clinical Trials INVANZ is not recommended in the treatment of meningitis in the pediatric population due to lack of Ticarcillin/ sufficient CSF penetration. INVANZ Ceftriaxone Clavulanate Adverse laboratory (n†=379) (n†=97) (n†=24) 8.5 Geriatric Use experiences Of the 1,835 patients in Phase 2b/3 trials treated with INVANZ, approximately 26 percent were 65 and ALT Increased 3.8 1.1 4.3 over, while approximately 12 percent were 75 and over. No overall differences in safety or effectiveness AST Increased 3.8 1.1 4.3 were observed between these patients and younger patients. Other reported clinical experience has not Neutrophil Count Decreased 5.8 3.1 0.0 identified differences in responses between the elderly and younger patients, but greater sensitivity of * Number of patients with laboratory adverse experiences/Number of patients with the laboratory test; where at least 300 patients had the test some older individuals cannot be ruled out. † Number of patients with one or more laboratory tests This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor Additional laboratory adverse experiences that were reported during therapy in !0.5% of patients renal function [see Dosage and Administration (2.2)]. treated with INVANZ in clinical trials include: alkaline phosphatase increased, eosinophil count increased, 8.6 Patients with Renal Impairment platelet count increased, white blood cell count decreased and urine protein present. Dosage adjustment is necessary in patients with creatinine clearance 30 mL/min or less [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

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8.7 Patients with Hepatic Impairment 12.3 Pharmacokinetics The pharmacokinetics of ertapenem in patients with hepatic impairment have not been established. Of Average plasma concentrations (mcg/mL) of ertapenem following a single 30-minute infusion of a 1 g the total number of patients in clinical trials, 37 patients receiving ertapenem 1 g daily and 36 patients intravenous (IV) dose and administration of a single 1 g intramuscular (IM) dose in healthy young adults receiving comparator drugs were considered to have Child-Pugh Class A, B, or C liver impairment. The are presented in Table 8. incidence of adverse experiences in patients with hepatic impairment was similar between the ertapenem group and the comparator groups. Table 8 Plasma Concentrations of Ertapenem in Adults After Single Dose Administration 10 OVERDOSAGE Average Plasma Concentrations (mcg/mL) Dose/Route 0.5 hr 1 hr 2 hr 4 hr 6 hr 8 hr 12 hr 18 hr 24 hr No specific information is available on the treatment of overdosage with INVANZ. Intentional 1 g IV* 155 115 83 48 31 20 9 3 1 overdosing of INVANZ is unlikely. Intravenous administration of INVANZ at a dose of 2 g over 30 min or 1 g IM 33 53 67 57 40 27 13 4 2 3 g over 1-2h in healthy adult volunteers resulted in an increased incidence of nausea. In clinical trials in *Infused at a constant rate over 30 minutes adults, inadvertent administration of three 1 g doses of INVANZ in a 24 hour period resulted in diarrhea and transient dizziness in one patient. In pediatric clinical trials, a single intravenous dose of 40 mg/kg up The area under the plasma concentration-time curve (AUC) of ertapenem in adults increased to a maximum of 2 g did not result in toxicity. less-than dose-proportional based on total ertapenem concentrations over the 0.5 to 2 g dose range, In the event of an overdose, INVANZ should be discontinued and general supportive treatment given whereas the AUC increased greater-than dose-proportional based on unbound ertapenem until renal elimination takes place. concentrations. Ertapenem exhibits non-linear pharmacokinetics due to concentration-dependent plasma INVANZ can be removed by hemodialysis; the plasma clearance of the total fraction of ertapenem protein binding at the proposed therapeutic dose [see Clinical Pharmacology (12.3)]. There is no was increased 30% in subjects with end-stage renal disease when hemodialysis (4 hour session) was accumulation of ertapenem following multiple IV or IM 1 g daily doses in healthy adults. performed immediately following administration. However, no information is available on the use of Average plasma concentrations (mcg/mL) of ertapenem in pediatric patients are presented in Table 9. hemodialysis to treat overdosage.

11 DESCRIPTION Table 9 Plasma Concentrations of Ertapenem in Pediatric Patients After Single IV* Dose Administration INVANZ (Ertapenem for Injection) is a sterile, synthetic, parenteral, 1-E methyl-carbapenem that is Age Group Dose Average Plasma Concentrations (mcg/mL) structurally related to beta-lactam antibiotics. 0.5 hr 1 hr 2 hr 4 hr 6 hr 8 hr 12 hr 24 hr 3 to 23 months Chemically, INVANZ is described as [4R-[3(3S*,5S*),4D,5E,6E(R*)]]-3-[[5-[[(3- 15 mg/kg† 103.8 57.3 43.6 23.7 13.5 8.2 2.5 - carboxyphenyl)amino]carbonyl]-3-pyrrolidinyl]thio]-6-(1-hydroxyethyl)-4-methyl-7-oxo-1- 20 mg/kg† 126.8 87.6 58.7 28.4 - 12.0 3.4 0.4 ‡ azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monosodium salt. Its molecular weight is 497.50. The 40 mg/kg 199.1 144.1 95.7 58.0 - 20.2 7.7 0.6 2 to 12 years empirical formula is C H N O SNa, and its structural formula is: † 22 24 3 7 15 mg/kg 113.2 63.9 42.1 21.9 12.8 7.6 3.0 - 20 mg/kg† 147.6 97.6 63.2 34.5 - 12.3 4.9 0.5 OH _ ‡ CH3 40 mg/kg 241.7 152.7 96.3 55.6 - 18.8 7.2 0.6 COO H H 13 to 17 years † H3C 20 mg/kg 170.4 98.3 67.8 40.4 - 16.0 7.0 1.1 S § Na+ 1 g 155.9 110.9 74.8 - 24.0 - 6.2 - N 40 mg/kg‡ 255.0 188.7 127.9 76.2 - 31.0 15.3 2.1 O _ * Infused at a constant rate over 30 minutes COO NH † + up to a maximum dose of 1 g/day N ‡ up to a maximum dose of 2 g/day H § 2 O Based on three patients receiving 1 g ertapenem who volunteered for pharmacokinetic assessment in one of the two safety and efficacy trials Ertapenem sodium is a white to off-white hygroscopic, weakly crystalline powder. It is soluble in water and 0.9% sodium chloride solution, practically insoluble in ethanol, and insoluble in isopropyl acetate and Absorption tetrahydrofuran. Ertapenem, reconstituted with 1% lidocaine HCl injection, USP (in saline without epinephrine), is INVANZ is supplied as sterile lyophilized powder for intravenous infusion after reconstitution with almost completely absorbed following intramuscular (IM) administration at the recommended dose of 1 g. appropriate diluent [see Dosage and Administration (2.7)] and transfer to 50 mL 0.9% Sodium Chloride The mean bioavailability is approximately 90%. Following 1 g daily IM administration, mean peak plasma Injection or for intramuscular injection following reconstitution with 1% lidocaine hydrochloride. Each vial concentrations (C ) are achieved in approximately 2.3 hours (T ). contains 1.046 grams ertapenem sodium, equivalent to 1 gram ertapenem. The sodium content is max max Distribution approximately 137 mg (approximately 6.0 mEq). Ertapenem is highly bound to human plasma proteins, primarily albumin. In healthy young adults, the Each vial of INVANZ contains the following inactive ingredients: 175 mg sodium bicarbonate and protein binding of ertapenem decreases as plasma concentrations increase, from approximately 95% sodium hydroxide to adjust pH to 7.5. bound at an approximate plasma concentration of <100 micrograms (mcg)/mL to approximately 85% bound at an approximate plasma concentration of 300 mcg/mL. 12 CLINICAL PHARMACOLOGY The apparent volume of distribution at steady state (Vss) of ertapenem in adults is approximately 12.1 Mechanism of Action 0.12 liter/kg, approximately 0.2 liter/kg in pediatric patients 3 months to 12 years of age and Ertapenem sodium is a carbapenem antibiotic [see Clinical Pharmacology (12.4)]. approximately 0.16 liter/kg in pediatric patients 13 to 17 years of age.

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The concentrations of ertapenem achieved in suction-induced skin blister fluid at each sampling point Gender on the third day of 1 g once daily IV doses are presented in Table 10. The ratio of AUC0-24 in skin blister The effect of gender on the pharmacokinetics of ertapenem was evaluated in healthy male (n=8) and fluid/AUC0-24 in plasma is 0.61. healthy female (n=8) subjects. The differences observed could be attributed to body size when body weight was taken into consideration. No dose adjustment is recommended based on gender. Geriatric Patients Table 10 Concentrations (mcg/mL) of Ertapenem in Adult Skin Blister Fluid at The impact of age on the pharmacokinetics of ertapenem was evaluated in healthy male (n=7) and each Sampling Point on the Third Day of 1-g Once Daily IV Doses healthy female (n=7) subjects t65 years of age. The total and unbound AUC increased 37% and 67%, 0.5 hr 1 hr 2 hr 4 hr 8 hr 12 hr 24 hr respectively, in elderly adults relative to young adults. These changes were attributed to age-related 7 12 17 24 24 21 8 changes in creatinine clearance. No dosage adjustment is necessary for elderly patients with normal (for their age) renal function. The concentration of ertapenem in breast milk from 5 lactating women with pelvic infections (5 to Pediatric Patients 14 days postpartum) was measured at random time points daily for 5 consecutive days following the last Plasma concentrations of ertapenem are comparable in pediatric patients 13 to 17 years of age and 1 g dose of intravenous therapy (3-10 days of therapy). The concentration of ertapenem in breast milk adults following a 1 g once daily IV dose. within 24 hours of the last dose of therapy in all 5 women ranged from <0.13 (lower limit of quantitation) to Following the 20 mg/kg dose (up to a maximum dose of 1 g), the pharmacokinetic parameter values in 0.38 mcg/mL; peak concentrations were not assessed. By day 5 after discontinuation of therapy, the level patients 13 to 17 years of age (N=6) were generally comparable to those in healthy young adults. of ertapenem was undetectable in the breast milk of 4 women and below the lower limit of quantitation Plasma concentrations at the midpoint of the dosing interval following a single 15 mg/kg IV dose of (<0.13 mcg/mL) in 1 woman. ertapenem in patients 3 months to 12 years of age are comparable to plasma concentrations at the Metabolism midpoint of the dosing interval following a 1 g once daily IV dose in adults [see Clinical Pharmacology In healthy young adults, after infusion of 1 g IV radiolabeled ertapenem, the plasma radioactivity (12.3)]. The plasma clearance (mL/min/kg) of ertapenem in patients 3 months to 12 years of age is consists predominantly (94%) of ertapenem. The major metabolite of ertapenem is the inactive ring- approximately 2-fold higher as compared to that in adults. At the 15 mg/kg dose, the AUC value (doubled opened derivative formed by hydrolysis of the beta-lactam ring. to model a twice daily dosing regimen, i.e., 30 mg/kg/day exposure) in patients 3 months to 12 years of Elimination age was comparable to the AUC value in young healthy adults receiving a 1 g IV dose of ertapenem. Ertapenem is eliminated primarily by the kidneys. The mean plasma half-life in healthy young adults is Drug Interactions approximately 4 hours and the plasma clearance is approximately 1.8 L/hour. The mean plasma half-life When ertapenem is co-administered with probenecid (500 mg p.o. every 6 hours), probenecid in pediatric patients 13 to 17 years of age is approximately 4 hours and approximately 2.5 hours in competes for active tubular secretion and reduces the renal clearance of ertapenem. Based on total pediatric patients 3 months to 12 years of age. ertapenem concentrations, probenecid increased the AUC of ertapenem by 25%, and reduced the Following the administration of 1 g IV radiolabeled ertapenem to healthy young adults, approximately plasma and renal clearance of ertapenem by 20% and 35%, respectively. The half-life of ertapenem was 80% is recovered in urine and 10% in feces. Of the 80% recovered in urine, approximately 38% is increased from 4.0 to 4.8 hours. excreted as unchanged drug and approximately 37% as the ring-opened metabolite. In vitro studies in human liver microsomes indicate that ertapenem does not inhibit metabolism In healthy young adults given a 1 g IV dose, the mean percentage of the administered dose excreted mediated by any of the following cytochrome p450 (CYP) isoforms: 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4. in urine was 17.4% during 0-2 hours postdose, 5.4% during 4-6 hours postdose, and 2.4% during 12-24 In vitro studies indicate that ertapenem does not inhibit P-glycoprotein-mediated transport of digoxin or hours postdose. vinblastine and that ertapenem is not a substrate for P-glycoprotein-mediated transport. Special Populations 12.4 Microbiology Renal Impairment Mechanism of Action Total and unbound fractions of ertapenem pharmacokinetics were investigated in 26 adult subjects (31 Ertapenem has in vitro activity against Gram-positive and Gram-negative aerobic and anaerobic to 80 years of age) with varying degrees of renal impairment. Following a single 1 g IV dose of bacteria. The bactericidal activity of ertapenem results from the inhibition of cell wall synthesis and is ertapenem, the unbound AUC increased 1.5-fold and 2.3-fold in subjects with mild renal impairment mediated through ertapenem binding to penicillin binding proteins (PBPs). In Escherichia coli, it has 2 2 (CLCR 60-90 mL/min/1.73 m ) and moderate renal impairment (CLCR 31-59 mL/min/1.73 m ), respectively, strong affinity toward PBPs 1a, 1b, 2, 3, 4 and 5 with preference for PBPs 2 and 3. compared with healthy young subjects (25 to 45 years of age). No dosage adjustment is necessary in Mechanism of Resistance 2 Ertapenem is stable against hydrolysis by a variety of beta-lactamases, including penicillinases, and patients with CLCR t31 mL/min/1.73 m . The unbound AUC increased 4.4-fold and 7.6-fold in subjects 2 cephalosporinases and extended spectrum beta-lactamases. Ertapenem is hydrolyzed by metallo-beta- with advanced renal impairment (CLCR 5-30 mL/min/1.73 m ) and end-stage renal disease (CLCR <10 mL/min/1.73 m2), respectively, compared with healthy young subjects. The effects of renal lactamases. impairment on AUC of total drug were of smaller magnitude. The recommended dose of ertapenem in Ertapenem has been shown to be active against most isolates of the following microorganisms both in 2 vitro and in clinical infections as described in the INDICATIONS AND USAGE section: adult patients with CLCR d30 mL/min/1.73 m is 0.5 grams every 24 hours. Following a single 1 g IV dose given immediately prior to a 4 hour hemodialysis session in 5 adult patients with end-stage renal disease, Gram-positive bacteria: approximately 30% of the dose was recovered in the dialysate. Dose adjustments are recommended for Staphylococcus aureus (methicillin susceptible isolates only) patients with severe renal impairment and end-stage renal disease [see Dosage and Administration Streptococcus agalactiae (2.4)]. There are no data in pediatric patients with renal impairment. Streptococcus pneumoniae (penicillin susceptible isolates only) Hepatic Impairment Streptococcus pyogenes The pharmacokinetics of ertapenem in patients with hepatic impairment have not been established. Gram-negative bacteria: However, ertapenem does not appear to undergo hepatic metabolism based on in vitro studies and Escherichia coli approximately 10% of an administered dose is recovered in the feces [see Clinical Pharmacology (12.3) Haemophilus influenzae (beta-lactamase negative isolates only) and Dosage and Administration (2.6)]. Klebsiella pneumoniae Moraxella catarrhalis Proteus mirabilis

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Anaerobic bacteria: Anaerobic Techniques: Bacteroides fragilis For anaerobic bacteria, the susceptibility to ertapenem as MICs can be determined by standardized Bacteroides distasonis test methods {3}. The MIC values obtained should be interpreted according to criteria provided in Table Bacteroides ovatus 11 and {4}. Bacteroides thetaiotaomicron Bacteroides uniformis Table 11 Clostridium clostridioforme Susceptibility Interpretive Criteria for Ertapenem Eubacterium lentum Pathogen Minimum Inhibitory Concentrations* Disk Diffusion Peptostreptococcus species MIC (Pg/mL) Zone Diameter (mm) Porphyromonas asaccharolytica S I R S I R Prevotella bivia Enterobacteriaceae d0.5 1 t2 t22 19-21 d18 † 4.0 16-18 The following in vitro data are available, but their clinical significance is unknown. At least 90% of Staphylococcus aureus d2.0 t8.0 t19 d15 Haemophilus spp.* d0.5 - - t19 - - the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the Streptococcus pneumoniae‡ d1.0 2 •4 - - - susceptible breakpoint for ertapenem. However, the efficacy of ertapenem in treating clinical infections Streptococcus spp. Beta Hemolytic d1.0 - - - - - due to these bacteria has not been established in adequate and well-controlled clinical trials: Group*,‡,§ Gram-positive bacteria: Streptococcus spp. Viridans Group* d1.0 - - - - - Staphylococcus epidermidis (methicillin susceptible isolates only) Anaerobes d4.0 8.0 t16.0 - - - Streptococcus pneumoniae (penicillin-intermediate isolates) * For some organism/antimicrobial combinations, the absence or rare occurrence of resistant strains precludes defining any results categories other than “susceptible”. For strains yielding results suggestive of a “non- Gram-negative bacteria: susceptible” category, organism identification and antimicrobial susceptibility test results should be confirmed. Citrobacter freundii † For oxacillin-susceptible S. aureus results for carbapenems, including ertapenem, if tested, should be reported Citrobacter koseri according to the results generated using routine interpretive criteria. For oxacillin-resistant S. aureus and coagulase Enterobacter aerogenes negative staphylococci, other beta lactam agents, including carbapenems, may appear active in vitro but are not effective clinically. Results for beta lactam agents other than cephalosporins with anti-MRSA activity should be Enterobacter cloacae reported as resistant or should not be reported. Haemophilus influenzae (beta-lactamase positive isolates only) ‡ S. pneumoniae penicillin MICs d2 mcg/mL indicate susceptibility to ertapenem. Haemophilus parainfluenzae § A beta hemolytic Streptococcus spp. (Groups A, B, C, G) isolate susceptible to penicillin (MIC d0.12 Pg/mL) can be Klebsiella oxytoca (excluding ESBL producing isolates) considered susceptible to ertapenem and need not be tested against ertapenem. Morganella morganii Proteus vulgaris A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial Providencia rettgeri compound at the infection site reaches the concentrations usually achievable. A report of “Intermediate” Providencia stuartii indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible Serratia marcescens to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical Anaerobic bacteria: applicability in body sites where the drug is physiologically concentrated or in situations where high Bacteroides vulgatus dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled Clostridium perfringens technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that Fusobacterium spp. the pathogen is not likely to be inhibited if the antimicrobial compound at the infection site reaches the Susceptibility Test Methods: concentrations usually achievable; other therapy should be selected. When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility Quality Control tests for antimicrobial drug products used in resident hospitals to the physician as periodic reports which Standardized susceptibility test procedures require the use of laboratory control microorganisms to describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the should aid the physician in selecting the most effective antimicrobial. individuals performing the test. Quality control microorganisms are specific strains of organisms with Dilution Techniques: intrinsic biological properties. QC strains are very stable strains which will give a standard and repeatable Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). susceptibility pattern. The specific strains used for microbiological quality control are not clinically These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs significant. Standard ertapenem powder should provide the following range of values noted in Table 12 should be determined using a standardized procedure. Standardized procedures are based on a broth and {4,5}. dilution method {1} or equivalent with standardized inoculum concentrations and standardized concentrations of ertapenem powder. The MIC values should be interpreted according to criteria provided in Table 11 and {4}. Table 12 Acceptable Quality Control Ranges for Ertapenem Diffusion Techniques: Microorganism Minimum Inhibitory Disk Diffusion Quantitative methods that require measurement of zone diameters also provide reproducible Concentrations Zone Diameter (mm) estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure MIC Range (Pg/mL) {2} requires the use of standardized inoculum concentrations. This procedure uses paper disks Escherichia coli ATCC 25922 0.004-0.016 29-36 impregnated with 10-Pg ertapenem to test the susceptibility of microorganisms to ertapenem. The disk Haemophilus influenzae ATCC 49766 0.015-0.06 27-33 Staphylococcus aureus ATCC 29213 0.06-0.25 - diffusion interpretive criteria should be interpreted according to criteria provided in Table 11 and {4}. Staphylococcus aureus ATCC 25923 - 24-31 Streptococcus pneumoniae ATCC 49619 0.03-0.25 28-35 Bacteroides fragilis ATCC 25285 0.06-0.5* -

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0.06-0.25† suspected osteomyelitis could be enrolled if all the infected bone was removed within 2 days of initiation Bacteroides thetaiotaomicron ATCC 29741 0.5-2.0* - of study therapy, and preferably within the prestudy period. Investigators had the option to add open-label 0.25-1.0† Eubacterium lentum ATCC 43055 0.5-4.0* - vancomycin if enterococci or methicillin-resistant Staphylococcus aureus (MRSA) were among the 0.5-2.0† pathogens isolated or if patients had a history of MRSA infection and additional therapy was indicated in * Quality control ranges for broth microdilution testing the opinion of the investigator. Two hundred and four (204) patients randomized to ertapenem and 202 † Quality control ranges for agar dilution testing patients randomized to piperacillin/tazobactam were clinically evaluable. The clinical success rates at 10 days posttherapy were 75.0% (153/204) for ertapenem and 70.8% (143/202) for piperacillin/tazobactam. Community Acquired Pneumonia 13 NONCLINICAL TOXICOLOGY Ertapenem was evaluated in adults for the treatment of community acquired pneumonia in two 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility randomized, double-blind, non-inferiority clinical trials. Both trials compared ertapenem (1 g parenterally No long-term studies in animals have been performed to evaluate the carcinogenic potential of once a day) with ceftriaxone (1 g parenterally once a day) and enrolled a total of 866 patients. Both ertapenem. regimens allowed the option to switch to oral amoxicillin/clavulanate for a total of 10 to 14 days of Ertapenem was neither mutagenic nor genotoxic in the following in vitro assays: alkaline elution/rat treatment (parenteral and oral). In the first trial the primary efficacy parameter was the clinical success hepatocyte assay, chromosomal aberration assay in Chinese hamster ovary cells, and TK6 human rate in the clinically evaluable population and success rates were 92.3% (168/182) for ertapenem and lymphoblastoid cell mutagenesis assay; and in the in vivo mouse micronucleus assay. 91.0% (183/201) for ceftriaxone at 7 to 14 days posttherapy (test-of-cure). In the second trial the primary In mice and rats, IV doses of up to 700 mg/kg/day (for mice, approximately 3 times the recommended efficacy parameter was the clinical success rate in the microbiologically evaluable population and human dose of 1 g based on body surface area and for rats, approximately 1.2 times the human success rates were 91% (91/100) for ertapenem and 91.8% (45/49) for ceftriaxone at 7 to 14 days exposure at the recommended dose of 1 g based on plasma AUCs) resulted in no effects on mating posttherapy (test-of-cure). performance, fecundity, fertility, or embryonic survival. Complicated Urinary Tract Infections Including Pyelonephritis 13.2 Animal Toxicology and/or Pharmacology Ertapenem was evaluated in adults for the treatment of complicated urinary tract infections including In repeat-dose studies in rats, treatment-related neutropenia occurred at every dose-level tested, pyelonephritis in two randomized, double-blind, non-inferiority clinical trials. Both trials compared including the lowest dose of 2 mg/kg (approximately 2% of the human dose on a body surface area ertapenem (1 g parenterally once a day) with ceftriaxone (1 g parenterally once a day) and enrolled a basis). total of 850 patients. Both regimens allowed the option to switch to oral ciprofloxacin (500 mg twice daily) Studies in rabbits and Rhesus monkeys were inconclusive with regard to the effect on neutrophil for a total of 10 to 14 days of treatment (parenteral and oral). The microbiological success rates counts. (combined trials) at 5 to 9 days posttherapy (test-of-cure) were 89.5% (229/256) for ertapenem and 91.1% (204/224) for ceftriaxone. Acute Pelvic Infections Including Endomyometritis, Septic Abortion and Post-Surgical Gynecological 14 CLINICAL STUDIES Infections 14.1 Adults Ertapenem was evaluated in adults for the treatment of acute pelvic infections in a randomized, Complicated Intra-Abdominal Infections double-blind, non-inferiority clinical trial. This trial compared ertapenem (1 g intravenously once a day) Ertapenem was evaluated in adults for the treatment of complicated intra-abdominal infections in a with piperacillin/tazobactam (3.375 g intravenously every 6 hours) for 3 to 10 days and enrolled 412 randomized, double-blind, non-inferiority clinical trial. This trial compared ertapenem (1 g intravenously patients including 350 patients with obstetric/postpartum infections and 45 patients with septic abortion. once a day) with piperacillin/tazobactam (3.375 g intravenously every 6 hours) for 5 to 14 days and The clinical success rates in the clinically evaluable population at 2 to 4 weeks posttherapy (test-of-cure) enrolled 665 patients with localized complicated appendicitis, and any other complicated intra-abdominal were 93.9% (153/163) for ertapenem and 91.5% (140/153) for piperacillin/tazobactam. infection including colonic, small intestinal, and biliary infections and generalized peritonitis. The Prophylaxis of Surgical Site Infections Following Elective Colorectal Surgery combined clinical and microbiologic success rates in the microbiologically evaluable population at 4 to 6 Ertapenem was evaluated in adults for prophylaxis of surgical site infection following elective weeks posttherapy (test-of-cure) were 83.6% (163/195) for ertapenem and 80.4% (152/189) for colorectal surgery in a multicenter, randomized, double-blind, non-inferiority clinical trial. This trial piperacillin/tazobactam. compared a single intravenous dose of ertapenem (1 g) versus cefotetan (2 g) administered over 30 Complicated Skin and Skin Structure Infections minutes, 1 hour before elective colorectal surgery. Test-of-prophylaxis was defined as no evidence of Ertapenem was evaluated in adults for the treatment of complicated skin and skin structure infections surgical site infection, post-operative anastomotic leak, or unexplained antibiotic use in the clinically in a randomized, double-blind, non-inferiority clinical trial. This trial compared ertapenem (1 g evaluable population up to and including at the 4-week posttreatment follow-up visit. The trial included intravenously once a day) with piperacillin/tazobactam (3.375 g intravenously every 6 hours) for 7 to 14 500 patients randomized to ertapenem and 502 patients randomized to cefotetan. The modified intent-to- days and enrolled 540 patients including patients with deep soft tissue abscess, posttraumatic wound treat (MITT) population consisted of 451 ertapenem patients and 450 cefotetan patients and included all infection and cellulitis with purulent drainage. The clinical success rates at 10 to 21 days posttherapy patients who were randomized, treated, and underwent elective colorectal surgery with adequate bowel (test-of-cure) were 83.9% (141/168) for ertapenem and 85.3% (145/170) for piperacillin/tazobactam. preparation. The clinically evaluable population was a subset of the MITT population and consisted of Diabetic Foot Infections patients who received a complete dose of study therapy no more than two hours prior to surgical incision Ertapenem was evaluated in adults for the treatment of diabetic foot infections without concomitant and no more than six hours before surgical closure. Clinically evaluable patients had sufficient information osteomyelitis in a multicenter, randomized, double-blind, non-inferiority clinical trial. This trial compared to determine outcome at the 4-week follow-up assessment and had no confounding factors that interfered ertapenem (1 g intravenously once a day) with piperacillin/tazobactam (3.375 g intravenously every 6 with the assessment of that outcome. Examples of confounding factors included prior or concomitant hours). Test-of-cure was defined as clinical response between treatment groups in the clinically evaluable antibiotic violations, the need for a second surgical procedure during the study period, and identification population at the 10-day posttherapy follow-up visit. The trial included 295 patients randomized to of a distant site infection with concomitant antibiotic administration and no evidence of subsequent wound ertapenem and 291 patients to piperacillin/tazobactam. Both regimens allowed the option to switch to oral infection. Three-hundred forty-six (346) patients randomized to ertapenem and 339 patients randomized amoxicillin/clavulanate for a total of 5 to 28 days of treatment (parenteral and oral). All patients were to cefotetan were clinically evaluable. The prophylactic success rates at 4 weeks posttreatment in the eligible to receive appropriate adjunctive treatment methods, such as debridement, as is typically required clinically evaluable population were 70.5% (244/346) for ertapenem and 57.2% (194/339) for cefotetan in the treatment of diabetic foot infections, and most patients received these treatments. Patients with (difference 13.3%, [95% C.I.: 6.1, 20.4], p<0.001). Prophylaxis failure due to surgical site infections

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occurred in 18.2% (63/346) ertapenem patients and 31.0% (105/339) cefotetan patients. Post-operative 16 HOW SUPPLIED/STORAGE AND HANDLING anastomotic leak occurred in 2.9% (10/346) ertapenem patients and 4.1% (14/339) cefotetan patients. 16.1 How Supplied Unexplained antibiotic use occurred in 8.4% (29/346) ertapenem patients and 7.7% (26/339) cefotetan INVANZ is supplied as a sterile lyophilized powder in single dose vials containing ertapenem for patients. Though patient numbers were small in some subgroups, in general, clinical response rates by intravenous infusion or for intramuscular injection as follows: age, gender, and race were consistent with the results found in the clinically evaluable population. In the No. 3843—1 g ertapenem equivalent MITT analysis, the prophylactic success rates at 4 weeks posttreatment were 58.3% (263/451) for NDC 0006-3843-71 in trays of 10 vials. ertapenem and 48.9% (220/450) for cefotetan (difference 9.4%, [95% C.I.: 2.9, 15.9], p=0.002). A INVANZ is supplied as a sterile lyophilized powder in single dose ADD-Vantage® vials containing statistically significant difference favoring ertapenem over cefotetan with respect to the primary endpoint ertapenem for intravenous infusion as follows: has been observed at a significance level of 5% in this trial. A second adequate and well-controlled trial to No. 3845—1 g ertapenem equivalent confirm these findings has not been conducted; therefore, the clinical superiority of ertapenem over NDC 0006-3845-71 in trays of 10 ADD-Vantage® vials. cefotetan has not been demonstrated. 16.2 Storage and Handling 14.2 Pediatric Patients Before reconstitution Ertapenem was evaluated in pediatric patients 3 months to 17 years of age in two randomized, multicenter clinical trials. Do not store lyophilized powder above 25qC (77qF). The first trial enrolled 404 patients and compared ertapenem (15 mg/kg intravenous (IV) every 12 Reconstituted and infusion solutions hours in patients 3 months to 12 years of age, and 1 g IV once a day in patients 13 to 17 years of age) to The reconstituted solution, immediately diluted in 0.9% Sodium Chloride Injection [see Dosage and ceftriaxone (50 mg/kg/day IV in two divided doses in patients 3 months to 12 years of age and Administration (2.7)], may be stored at room temperature (25°C) and used within 6 hours or stored for 24 50 mg/kg/day IV as a single daily dose in patients 13 to 17 years of age) for the treatment of complicated hours under refrigeration (5°C) and used within 4 hours after removal from refrigeration. Solutions of urinary tract infection (UTI), skin and soft tissue infection (SSTI), or community-acquired pneumonia INVANZ should not be frozen. (CAP). Both regimens allowed the option to switch to oral amoxicillin/clavulanate for a total of up to 14 days of treatment (parenteral and oral). The microbiological success rates in the evaluable per 17 PATIENT COUNSELING INFORMATION protocol (EPP) analysis in patients treated for UTI were 87.0% (40/46) for ertapenem and 90.0% (18/20) 17.1 Instructions for Patients for ceftriaxone. The clinical success rates in the EPP analysis in patients treated for SSTI were 95.5% Patients should be advised that allergic reactions, including serious allergic reactions could occur and (64/67) for ertapenem and 100% (26/26) for ceftriaxone, and in patients treated for CAP were 96.1% that serious reactions may require immediate treatment. Advise patients to report any previous (74/77) for ertapenem and 96.4% (27/28) for ceftriaxone. hypersensitivity reactions to INVANZ, other beta-lactams or other allergens. The second trial enrolled 112 patients and compared ertapenem (15 mg/kg IV every 12 hours in Patients should be counseled to inform their physician if they are taking valproic acid or divalproex patients 3 months to 12 years of age, and 1 g IV once a day in patients 13 to 17 years of age) to sodium. Valproic acid concentrations in the blood may drop below the therapeutic range upon co- ticarcillin/clavulanate (50 mg/kg for patients 60 kg or 3.0 g for patients !60 kg, 4 or 6 times a day) up to administration with INVANZ. If treatment with INVANZ is necessary and continued, alternative or 14 days for the treatment of complicated intra-abdominal infections (IAI) and acute pelvic infections (API). supplemental anti-convulsant medication to prevent and/or treat seizures may be needed. In patients treated for IAI (primarily patients with perforated or complicated appendicitis), the clinical Patients should be counseled that antibacterial drugs including INVANZ should only be used to treat success rates were 83.7% (36/43) for ertapenem and 63.6% (7/11) for ticarcillin/clavulanate in the EPP bacterial infections. They do not treat viral infections (e.g., the common cold). When INVANZ is analysis. In patients treated for API (post-operative or spontaneous obstetrical endomyometritis, or septic prescribed to treat a bacterial infection, patients should be told that although it is common to feel better abortion), the clinical success rates were 100% (23/23) for ertapenem and 100% (4/4) for early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not ticarcillin/clavulanate in the EPP analysis. completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by INVANZ or 15 REFERENCES other antibacterial drugs in the future. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is 1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody Tests for Bacteria that Grow Aerobically. 9th Edition; CLSI Document M7-A9. CLSI, Wayne, PA, 2012. stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. 2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Susceptibility Tests. 11th Edition; CLSI Document M2-A11. CLSI, Wayne, PA, 2012. 3. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria – 7th Edition; CLSI Document M11-A7. CLSI, Wayne, PA, 2007. 4. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial nd By: Laboratoires Merck Sharp & Dohme-Chibret Susceptibility Testing – 22 Informational Supplement. CLSI Document M100-S22. CLSI, Wayne, PA, Clermont Ferrand Cedex 9, 63963, France 2012. 5. Clinical and Laboratory Standards Institute (CLSI, formerly NCCLS). Performance Standards for Copyright ” 2001, 2007, 2011 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. Antimicrobial Susceptibility of Anaerobic Bacteria; Informational Supplement. CLSI Document M11-S1. All rights reserved CLSI, Wayne, PA, 2010. US Patent Nos.: 5,478,820; 5,952,323; 5,652,233

Revised 06/2013

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