Ertapenem

1 INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of Ertapenem for Injection and other antibacterial drugs, Ertapenem for Injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Treatment Ertapenem for Injection is indicated for the treatment of adult patients and pediatric patients (3 months of age and older) with the following moderate to severe infections caused by susceptible isolates of the designated microorganisms [see Dosage and Administration (2) ]. Ertapenem for Injection is a penem antibacterial indicated in adult patients and pediatric patients (3 months of age and older) for the treatment of the following moderate to severe infections caused by susceptible bacteria: • Complicated intra-abdominal infections. ( 1.1 ) • Complicated skin and skin structure infections, including diabetic foot infections without osteomyelitis. ( 1.2 ) • Community-acquired pneumonia. ( 1.3 ) • Complicated urinary tract infections including pyelonephritis. ( 1.4 ) • Acute pelvic infections including postpartum endomyometritis, septic abortion and post surgical gynecologic infections. ( 1.5 ) Ertapenem for Injection is indicated in adults for the prophylaxis of surgical site infection following elective colorectal surgery. ( 1.6 ) 1.1 Complicated Intra-Abdominal Infections Ertapenem for Injection is indicated for the treatment of complicated intra-abdominal infections due to Escherichia coli , Clostridium clostridioforme , Eubacterium lentum , Peptostreptococcus species, Bacteroides fragilis , Bacteroides distasonis , Bacteroides ovatus , Bacteroides thetaiotaomicron , or Bacteroides uniformis . 1.2 Complicated Skin and Skin Structure Infections, Including Diabetic Foot Infections without Osteomyelitis Ertapenem for Injection is indicated for the treatment of complicated skin and skin structure infections, including diabetic foot infections without osteomyelitis due to Staphylococcus aureus (methicillin susceptible isolates only), Streptococcus agalactiae , Streptococcus pyogenes , Escherichia coli , Klebsiella pneumoniae , Proteus mirabilis , Bacteroides fragilis , Peptostreptococcus species, Porphyromonas asaccharolytica , or Prevotella bivia . Ertapenem for Injection has not been studied in diabetic foot infections with concomitant osteomyelitis [see Clinical Studies (14) ]. 1.3 Community Acquired Pneumonia Ertapenem for Injection is indicated for the treatment of community acquired pneumonia due to Streptococcus 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 Ertapenem for Injection is indicated for the treatment of complicated urinary tract infections including pyelonephritis due to Escherichia coli , including cases with concurrent bacteremia, or Klebsiella pneumoniae . 1.5 Acute Pelvic Infections Including Postpartum Endomyometritis, Septic Abortion and Post Surgical Gynecologic Infections Ertapenem for Injection is indicated for the treatment of acute pelvic infections including postpartum endomyometritis, septic abortion and post surgical gynecological infections due to Streptococcus agalactiae, Escherichia coli , Bacteroides fragilis, Porphyromonas asaccharolytica, Peptostreptococcus species, or Prevotella bivia . Prevention Ertapenem for Injection is indicated in adults for: 1.6 Prophylaxis of Surgical Site Infection Following Elective Colorectal Surgery Ertapenem for Injection is indicated for the prevention of surgical site infection following elective colorectal surgery.

5 WARNINGS AND PRECAUTIONS • Serious hypersensitivity (anaphylactic) reactions have been reported in patients receiving β-lactams. ( 5.1 ) • Seizures and other central nervous system adverse experiences have been reported during treatment. ( 5.2 ) • Co-administration of Ertapenem for Injection with valproic acid or divalproex sodium reduces the serum concentration of valproic acid potentially increasing the risk of breakthrough seizures. ( 5.3 ) • Clostridium difficile -associated diarrhea (ranging from mild diarrhea to fatal colitis): Evaluate if diarrhea occurs. ( 5.4 ) • Caution should be taken when administering Ertapenem for Injection intramuscularly to avoid inadvertent injection into a blood vessel. ( 5.5 ) 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 Ertapenem for Injection, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, other beta-lactams and other allergens. If an allergic reaction to Ertapenem for Injection occurs, discontinue the drug immediately. Serious anaphylactic reactions require immediate emergency treatment as clinically indicated. 5.2 Seizure Potential Seizures and other central nervous system (CNS) adverse experiences have been reported during treatment with Ertapenem for Injection [see Adverse Reactions (6.1) ] . During clinical investigations in adult patients treated with Ertapenem for Injection (1 g once a day), seizures, irrespective of drug relationship, occurred in 0.5% of patients during study therapy plus 14-day follow-up period [see Adverse Reactions (6.1) ] . These experiences have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) and/or compromised renal function. Close adherence to the recommended dosage regimen is urged, especially in patients with known factors that predispose to convulsive activity. Anticonvulsant therapy should be continued in patients with known seizure disorders. If focal tremors, myoclonus, or seizures occur, patients should be evaluated neurologically, placed on anticonvulsant therapy if not already instituted, and the dosage of Ertapenem for Injection re-examined to determine whether it should be decreased or discontinued. 5.3 Interaction with Valproic Acid 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 concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. Increasing the dose of valproic acid or divalproex sodium may not be sufficient to overcome this interaction. The concomitant use of ertapenem and valproic acid/divalproex sodium is generally not recommended. Anti-bacterials other than carbapenems should be considered to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium. If administration of Ertapenem for Injection is necessary, supplemental anti-convulsant therapy should be considered [see Drug Interactions (7.2) ] . 5.4 Clostridium difficile -Associated Diarrhea (CDAD) CDAD has been reported with use of nearly all antibacterial agents, including ertapenem, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of 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 infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against Clostridium difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of Clostridium difficile , and surgical evaluation should be instituted as clinically indicated. 5.5 Caution with Intramuscular Administration Caution should be taken when administering Ertapenem for Injection intramuscularly to avoid inadvertent injection into a blood vessel [see Dosage and Administration (2.7) ] . 5.6 Development of Drug-Resistant Bacteria As with other antibiotics, prolonged use of Ertapenem for Injection may result in overgrowth of non-susceptible organisms. Repeated evaluation of the patient’s condition is essential. If superinfection occurs during therapy, appropriate measures should be taken. Prescribing Ertapenem for Injection in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. 5.7 Laboratory Tests While Ertapenem for Injection possesses toxicity similar to the beta-lactam group of antibiotics, periodic assessment of organ system function, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy.

6 ADVERSE REACTIONS The following are described in greater detail in the Warnings and Precautions section. • Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] • Seizure Potential [see Warnings and Precautions (5.2) ] • Interaction with Valproic Acid [see Warnings and Precautions (5.3) ] • Clostridium difficile -Associated Diarrhea (CDAD) [see Warnings and Precautions (5.4) ] • Caution with Intramuscular Administration [see Warnings and Precautions (5.5) ] • Development of Drug-Resistant Bacteria [see Warnings and Precautions (5.6) ] • Laboratory Tests [see Warnings and Precautions (5.7) ] Adults: The most common adverse reactions (≥5%) in patients treated with Ertapenem for Injection, including those who were switched to therapy with an oral antimicrobial, were diarrhea, nausea, headache and infused vein complication. ( 6.1 ) In the prophylaxis indication the overall adverse experience profile was generally comparable to that observed for ertapenem in other clinical trials. ( 6.1 ) Pediatrics: Adverse reactions in this population were comparable to adults. The most common adverse reactions (≥5%) in pediatric patients treated with Ertapenem for Injection, including those who were switched to therapy with an oral antimicrobial, were diarrhea, vomiting and infusion site pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adults Receiving Ertapenem for Injection as a Treatment Regimen Clinical trials enrolled 1954 patients treated with Ertapenem for Injection; in some of the clinical trials, parenteral therapy was followed by a switch to an appropriate oral antimicrobial [see Clinical Studies (14) ] . Most adverse experiences reported in these clinical trials were described as mild to moderate in severity. Ertapenem for Injection was discontinued due to adverse experiences in 4.7% of patients. Table 3 shows the incidence of adverse experiences reported in ≥2% of patients in these trials. The most common drug-related adverse experiences in patients treated with Ertapenem for Injection, including those who were switched to therapy with an oral antimicrobial, were diarrhea (5.5%), infused vein complication (3.7%), nausea (3.1%), headache (2.2%), and vaginitis in females (2.1%). Table 3: Incidence (%) of Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in ≥2% of Adult Patients Treated With Ertapenem for Injection in Clinical Trials Ertapenem for Injection Includes Phase IIb/III Complicated intra-abdominal infections, Complicated skin and skin structure infections and Acute pelvic infections trials 1 g daily Piperacillin/ Tazobactam 3.375 g q6h Ertapenem for Injection Includes Phase IIb/III Community acquired pneumonia and Complicated urinary tract infections, and Phase IIa trials 1 g daily Ceftriaxone 1 or 2 g daily Adverse Events (N=802) (N=774) (N=1152) (N=942) Local: Infused vein complication 7.1 7.9 5.4 6.7 Systemic: Death 2.5 1.6 1.3 1.6 Edema/swelling 3.4 2.5 2.9 3.3 Fever 5 6.6 2.3 3.4 Abdominal pain 3.6 4.8 4.3 3.9 Hypotension 2 1.4 1 1.2 Constipation 4 5.4 3.3 3.1 Diarrhea 10.3 12.1 9.2 9.8 Nausea 8.5 8.7 6.4 7.4 Vomiting 3.7 5.3 4 4 Altered mental status Includes agitation, confusion, disorientation, decreased mental acuity, changed mental status, somnolence, stupor 5.1 3.4 3.3 2.5 Dizziness 2.1 3 1.5 2.1 Headache 5.6 5.4 6.8 6.9 Insomnia 3.2 5.2 3 4.1 Dyspnea 2.6 1.8 1 2.4 Pruritus 2 2.6 1 1.9 Rash 2.5 3.1 2.3 1.5 Vaginitis 1.4 1 3.3 3.7 In patients treated for complicated intra-abdominal infections, death occurred in 4.7% (15/316) of patients receiving Ertapenem for Injection and 2.6% (8/307) of patients receiving comparator drug. These deaths occurred in patients with significant co-morbidity and/or severe baseline infections. Deaths were considered unrelated to study drugs by investigators. In clinical trials, seizure was reported during study therapy plus 14-day follow-up period in 0.5% of patients treated with Ertapenem for Injection, 0.3% of patients treated with piperacillin/tazobactam and 0% of patients treated with ceftriaxone [see Warnings and Precautions (5.2) ] . Additional adverse experiences that were reported with Ertapenem for Injection with an incidence >0.1% within each body system are listed below Body as a Whole: abdominal distention, pain, chills, septicemia, septic shock, dehydration, gout, malaise, asthenia/fatigue, necrosis, candidiasis, weight loss, facial edema, injection site induration, injection site pain, extravasation, phlebitis/thrombophlebitis, flank pain, syncope Cardiovascular System: heart failure, hematoma, chest pain, hypertension, tachycardia, cardiac arrest, bradycardia, arrhythmia, atrial fibrillation, heart murmur, ventricular tachycardia, asystole, subdural hemorrhage Digestive System: acid regurgitation, oral candidiasis, dyspepsia, gastrointestinal hemorrhage, anorexia, flatulence, C. difficile -associated diarrhea, stomatitis, dysphagia, hemorrhoids, ileus, cholelithiasis, duodenitis, esophagitis, gastritis, jaundice, mouth ulcer, pancreatitis, pyloric stenosis Musculoskeletal System: leg pain Nervous System & Psychiatric: anxiety, nervousness, seizure [see Warnings and Precautions (5.2) ] , tremor, depression, hypesthesia, spasm, paresthesia, aggressive behavior, vertigo Respiratory System: cough, pharyngitis, rales/rhonchi, respiratory distress, pleural effusion, hypoxemia, bronchoconstriction, pharyngeal discomfort, epistaxis, pleuritic pain, asthma, hemoptysis, hiccups, voice disturbance Skin & Skin Appendage: erythema, sweating, dermatitis, desquamation, flushing, urticaria Special Senses: taste perversion Urogenital System: renal impairment, oliguria/anuria, vaginal pruritus, hematuria, urinary retention, bladder dysfunction, vaginal candidiasis, vulvovaginitis. In a clinical trial for the treatment of diabetic foot infections in which 289 adult diabetic patients were treated with Ertapenem for Injection, the adverse experience profile was generally similar to that seen in previous clinical trials. Prophylaxis of Surgical Site Infection following Elective Colorectal Surgery In a clinical trial in adults for the prophylaxis of surgical site infection following elective colorectal surgery in which 476 patients received a 1 g dose of Ertapenem for Injection 1 hour prior to surgery and were then followed for safety 14 days post surgery, the overall adverse experience profile was generally comparable to that observed for Ertapenem for Injection in previous clinical trials. Table 4 shows the incidence of adverse experiences other than those previously described above for Ertapenem for Injection that were reported regardless of causality in ≥2% of patients in this trial. Table 4: Incidence (%) of Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in ≥2% of Adult Patients Treated With Ertapenem for Injection for Prophylaxis of Surgical Site Infections Following Elective Colorectal Surgery Adverse Events Ertapenem for Injection 1 g (N = 476) Cefotetan 2 g (N = 476) Anemia 5.7 6.9 Small intestinal obstruction 2.1 1.9 Pneumonia 2.1 4 Postoperative infection 2.3 4 Urinary tract infection 3.8 5.5 Wound infection 6.5 12.4 Wound complication 2.9 2.3 Atelectasis 3.4 1.9 Additional adverse experiences that were reported in this prophylaxis trial with Ertapenem for Injection, regardless of causality, with an incidence >0.5% within each body system are listed below: Gastrointestinal Disorders: C. difficile infection or colitis, dry mouth, hematochezia General Disorders and Administration Site Condition: crepitations Infections and Infestations: cellulitis, abdominal abscess, fungal rash, pelvic abscess Injury, Poisoning and Procedural Complications: incision site complication, incision site hemorrhage, intestinal stoma complication, anastomotic leak, seroma, wound dehiscence, wound secretion Musculoskeletal and Connective Tissue Disorders: muscle spasms Nervous System Disorders: cerebrovascular accident Renal and Urinary Disorders: dysuria, pollakiuria Respiratory, Thoracic and Mediastinal Disorders: crackles lung, lung infiltration, pulmonary congestion, pulmonary embolism, wheezing. Pediatric Patients Receiving Ertapenem for Injection as a Treatment Regimen Clinical trials enrolled 384 patients treated with Ertapenem for Injection; in some of the clinical trials, parenteral therapy was followed by a switch to an appropriate oral antimicrobial [see Clinical Studies (14) ] . The overall adverse experience profile in pediatric patients is comparable to that in adult patients. Table 5 shows the incidence of adverse experiences reported in ≥2% of pediatric patients in clinical trials. The most common drug-related adverse experiences in pediatric patients treated with Ertapenem for Injection, including those who were switched to therapy with an oral antimicrobial, were diarrhea (6.5%), infusion site pain (5.5%), infusion site erythema (2.6%), vomiting (2.1%). Table 5: Incidence (%) of Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in ≥2% of Pediatric Patients Treated With Ertapenem for Injection in Clinical Trials Ertapenem for Injection 1, Includes Phase IIb Acute pelvic infections and Complicated intra-abdominal infections trials in which patients 3 months to 12 years of age received Ertapenem for Injection 15 mg/kg I.V. twice daily up to a maximum of 1 g and patients 13 to 17 years of age received Ertapenem for Injection 1 g I.V. daily or ticarcillin/clavulanate 50 mg/kg for patients 60 kg, 4 or 6 times a day. Ceftriaxone Includes Phase IIb Complicated skin and skin structure infections, Community acquired pneumonia and Complicated urinary tract infections trials in which patients 3 months to 12 years of age received Ertapenem for Injection 15 mg/kg I.V. twice daily up to a maximum of 1 g or ceftriaxone 50 mg/kg/day I.V. in two divided doses up to a maximum of 2 g, and patients 13 to 17 years of age received Ertapenem for Injection 1 g I.V. daily or ceftriaxone 50 mg/kg/day I.V. in a single daily dose. Ticarcillin/ Clavulanate Adverse Events (N=384) (N=100) (N=24) Local: Infusion Site Erythema 3.9 3 8.3 Infusion Site Pain 7 4 20.8 Systemic: Abdominal Pain 4.7 3 4.2 Constipation 2.3 0 0 Diarrhea 11.7 17 4.2 Loose Stools 2.1 0 0 Vomiting 10.2 11 8.3 Pyrexia 4.9 6 8.3 Upper Respiratory Tract Infection 2.3 3 0 Headache 4.4 4 0 Cough 4.4 3 0 Diaper Dermatitis 4.7 4 0 Rash 2.9 2 8.3 Additional adverse experiences that were reported with Ertapenem for Injection with an incidence >0.5% within each body system are listed below: Gastrointestinal Disorders: nausea General Disorders and Administration Site Condition: hypothermia, chest pain, upper abdominal pain; infusion site pruritus, induration, phlebitis, swelling, and warmth Infections and Infestations: candidiasis, oral candidiasis, viral pharyngitis, herpes simplex, ear infection, abdominal abscess Metabolism and Nutrition Disorders: decreased appetite Musculoskeletal and Connective Tissue Disorders: arthralgia Nervous System Disorders: dizziness, somnolence Psychiatric Disorders: insomnia Reproductive System and Breast Disorders: genital rash Respiratory, Thoracic and Mediastinal Disorders: wheezing, nasopharyngitis, pleural effusion, rhinitis, rhinorrhea Skin and Subcutaneous Tissue Disorders: dermatitis, pruritus, rash erythematous, skin lesion Vascular Disorders: phlebitis. 6.2 Post-Marketing Experience The following additional adverse reactions have been identified during the post-approval use of Ertapenem for Injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal Disorders: teeth staining Immune System Disorders: anaphylaxis including anaphylactoid reactions Musculoskeletal and Connective Tissue Disorders: muscular weakness Nervous System Disorders: coordination abnormal, depressed level of consciousness, dyskinesia, gait disturbance, myoclonus, tremor Psychiatric Disorders: altered mental status (including aggression, delirium), hallucinations Skin and Subcutaneous Tissue Disorders: Acute Generalized Exanthematous Psutulosis (AGEP), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS syndrome) 6.3 Adverse Laboratory Changes in Clinical Trials Adults Receiving Ertapenem for Injection as Treatment Regimen Laboratory adverse experiences that were reported during therapy in ≥2% of adult patients treated with Ertapenem for Injection in clinical trials are presented in Table 6 . Drug-related laboratory adverse experiences that were reported during therapy in ≥2% of adult patients treated with Ertapenem for Injection, including those who were switched to therapy with an oral antimicrobial, in clinical trials were ALT increased (6%), AST increased (5.2%), serum alkaline phosphatase increased (3.4%), and platelet count increased (2.8%). Ertapenem for Injection was discontinued due to laboratory adverse experiences in 0.3% of patients. Table 6: Incidence Number of patients with laboratory adverse experiences/Number of patients with the laboratory test (%) of Laboratory Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in ≥2% of Adult Patients Treated With Ertapenem for Injection in Clinical Trials Ertapenem for Injection Includes Phase IIb/III Complicated intra-abdominal infections, Complicated skin and skin structure infections and Acute pelvic infections trials 1 g daily Piperacillin/ Tazobactam 3.375 g q6h Ertapenem for Injection Includes Phase IIb/III Community acquired pneumonia and Complicated urinary tract infections, and Phase IIa trials 1 g daily Ceftriaxone 1 or 2 g daily Adverse laboratory experiences (n Number of patients with one or more laboratory tests =766) (n =755) (n =1122) (n =920) ALT increased 8.8 7.3 8.3 6.9 AST increased 8.4 8.3 7.1 6.5 Serum alkaline phosphatase increased 6.6 7.2 4.3 2.8 Eosinophils increased 1.1 1.1 2.1 1.8 Hematocrit decreased 3 2.9 3.4 2.4 Hemoglobin decreased 4.9 4.7 4.5 3.5 Platelet count increased 6.5 6.3 4.3 3.5 Urine RBCs increased 2.5 2.9 1.1 1 Urine WBCs increased 2.5 3.2 1.6 1.1 Additional laboratory adverse experiences that were reported during therapy in >0.1% of patients treated with Ertapenem for Injection in clinical trials include: increases in serum creatinine, serum glucose, BUN, total, direct and indirect serum bilirubin, serum sodium and potassium, PT and PTT; decreases in serum potassium, serum albumin, WBC, platelet count, and segmented neutrophils. In a clinical trial for the treatment of diabetic foot infections in which 289 adult diabetic patients were treated with Ertapenem for Injection, the laboratory adverse experience profile was generally similar to that seen in previous clinical trials. Prophylaxis of Surgical Site Infection following Elective Colorectal Surgery In a clinical trial in adults for the prophylaxis of surgical site infection following elective colorectal surgery in which 476 patients received a 1 g dose of Ertapenem for Injection 1 hour prior to surgery and were then followed for safety 14 days post surgery, the overall laboratory adverse experience profile was generally comparable to that observed for Ertapenem for Injection in previous clinical trials. Pediatric Patients Receiving Ertapenem for Injection as a Treatment Regimen Laboratory adverse experiences that were reported during therapy in ≥2% of pediatric patients treated with Ertapenem for Injection in clinical trials are presented in Table 7 . Drug-related laboratory adverse experiences that were reported during therapy in ≥2% of pediatric patients treated with Ertapenem for Injection, including those who were switched to therapy with an oral antimicrobial, in clinical trials were neutrophil count decreased (3%), ALT increased (2.2%), and AST increased (2.1%). Table 7: Incidence Number of patients with laboratory adverse experiences/Number of patients with the laboratory test; where at least 300 patients had the test (%) of Specific Laboratory Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in ≥2% of Pediatric Patients Treated With Ertapenem for Injection in Clinical Trials Ertapenem for Injection Ceftriaxone Ticarcillin/ Clavulanate Adverse laboratory experiences (n Number of patients with one or more laboratory tests =379) (n =97) (n =24) ALT Increased 3.8 1.1 4.3 AST Increased 3.8 1.1 4.3 Neutrophil Count Decreased 5.8 3.1 0 Additional laboratory adverse experiences that were reported during therapy in >0.5% of patients treated with Ertapenem for Injection in clinical trials include: alkaline phosphatase increased, eosinophil count increased, platelet count increased, white blood cell count decreased and urine protein present.

8 USE IN SPECIFIC POPULATIONS • Renal Impairment: Dose adjustment is necessary, if creatinine clearance is ≤30 mL/min/1.73 m 2 . ( 2.4 , 8.6 , 12.3 ) 8.1 Pregnancy Risk Summary Available data from a small number of postmarketing cases with Ertapenem for Injection use in pregnancy are insufficient to inform any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies after intravenous administration of ertapenem during the period of organogenesis, there was no evidence of developmental malformations in rats at systemic exposures (AUC) up to approximately 1.2 times the human exposure at the maximum recommended human dose (MRHD) and in mice at doses up to approximately 3 times the MRHD based on body surface area comparison. In pregnant rats administered ertapenem during organogenesis through lactation, fetal toxicity, developmental delays, and impaired reproduction did not occur in first generation offspring at systemic exposures (AUC) approximately 1.2 times the human exposure at the MRHD (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In pregnant rats, intravenous administration of ertapenem dosages of up to 700 mg/kg/day (approximately 1.2 times the MRHD based on AUC) during the period of organogenesis (gestation days [GD] 6-20) revealed no maternal or embryofetal effects. Pregnant mice intravenously administered ertapenem dosages of up to 700 mg/kg/day (approximately 3 times the MRHD based on body surface area comparison) during the period of organogenesis (GD 6-15) showed slight decreases in average fetal weight and an associated decrease in the average number of ossified sacrocaudal vertebrae. There were no maternal effects at any dosage. In a pre-postnatal study in rats, ertapenem administered to pregnant rats at dosages up to 700 mg/kg/day (approximately 1.2 times the MRHD based on AUC) during organogenesis through lactation, (GD 6 until Lactation Day (LD) 20) did not result in fetal toxicity, developmental delays, or impaired reproduction in first generation offspring, and fetal deaths and malformations were not increased in second generation offspring. 8.2 Lactation Risk Summary Ertapenem is present in human milk (see Data) . There are no data on the effects on the breastfed infant or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Ertapenem for Injection and any potential adverse effects on the breastfed infant from Ertapenem for Injection or from the underlying maternal condition. Data The concentration of ertapenem in breast milk from 5 lactating women with pelvic infections (5 to 14 days postpartum) measured at random time points daily for 5 consecutive days following the last 1 g dose of intravenous therapy (3 to 10 days of therapy) showed low levels. The concentration of ertapenem in breast milk within 24 hours of the last dose of therapy in all 5 women ranged from (<0.13 (lower limit of quantitation) to 0.38 mcg/ml), although peak concentrations were not assessed. By day 5 after discontinuation of therapy, the level of ertapenem was undetectable in the breast milk of 4 women and below the lower limit of quantitation (<0.13 mcg/mL) in 1 woman. The concentration of ertapenem in transitional milk observed in this study may not reflect the concentration of ertapenem in mature milk. 8.4 Pediatric Use Safety and effectiveness of Ertapenem for Injection in pediatric patients 3 months to 17 years of age are supported 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 [see Indications and Usage ( 1.1 ), ( 1.2 ), ( 1.3 ), ( 1.4 ) and ( 1.5 ) and Clinical Studies (14.2) ] . Ertapenem for Injection is not recommended in infants under 3 months of age as no data are available. Ertapenem for Injection is not recommended in the treatment of meningitis in the pediatric population due to lack of sufficient CSF penetration. 8.5 Geriatric Use Of the 1,835 patients in Phase 2b/3 trials treated with Ertapenem for Injection, approximately 26 percent were 65 and over, while approximately 12 percent were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 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 renal function [see Dosage and Administration (2.2) ] . 8.6 Patients with Renal Impairment 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) ] . 8.7 Patients with Hepatic Impairment The pharmacokinetics of ertapenem in patients with hepatic impairment have not been established. Of the total number of patients in clinical trials, 37 patients receiving ertapenem 1 g daily and 36 patients receiving comparator drugs were considered to have Child-Pugh Class A, B, or C liver impairment. The incidence of adverse experiences in patients with hepatic impairment was similar between the ertapenem group and the comparator groups.

8.1 Pregnancy Risk Summary Available data from a small number of postmarketing cases with Ertapenem for Injection use in pregnancy are insufficient to inform any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies after intravenous administration of ertapenem during the period of organogenesis, there was no evidence of developmental malformations in rats at systemic exposures (AUC) up to approximately 1.2 times the human exposure at the maximum recommended human dose (MRHD) and in mice at doses up to approximately 3 times the MRHD based on body surface area comparison. In pregnant rats administered ertapenem during organogenesis through lactation, fetal toxicity, developmental delays, and impaired reproduction did not occur in first generation offspring at systemic exposures (AUC) approximately 1.2 times the human exposure at the MRHD (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In pregnant rats, intravenous administration of ertapenem dosages of up to 700 mg/kg/day (approximately 1.2 times the MRHD based on AUC) during the period of organogenesis (gestation days [GD] 6-20) revealed no maternal or embryofetal effects. Pregnant mice intravenously administered ertapenem dosages of up to 700 mg/kg/day (approximately 3 times the MRHD based on body surface area comparison) during the period of organogenesis (GD 6-15) showed slight decreases in average fetal weight and an associated decrease in the average number of ossified sacrocaudal vertebrae. There were no maternal effects at any dosage. In a pre-postnatal study in rats, ertapenem administered to pregnant rats at dosages up to 700 mg/kg/day (approximately 1.2 times the MRHD based on AUC) during organogenesis through lactation, (GD 6 until Lactation Day (LD) 20) did not result in fetal toxicity, developmental delays, or impaired reproduction in first generation offspring, and fetal deaths and malformations were not increased in second generation offspring.