Ertapenem Drug Information

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. 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 ≥2.0% 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 ≥2.0% of Adult Patients Treated With Ertapenem for Injection in Clinical Trials * Includes Phase IIb/III Complicated intra-abdominal infections, Complicated skin and skin structure infections and Acute pelvic infections trials † Includes Phase IIb/III Community acquired pneumonia and Complicated urinary tract infections, and Phase IIa trials ‡ Includes agitation, confusion, disorientation, decreased mental acuity, changed mental status, somnolence, stupor Adverse Events Ertapenem for Injection * 1 gram daily (N=802) Piperacillin/Tazobactam* 3.375 grams q6h (N=774) Ertapenem for Injection † 1 gram daily (N=1152) Ceftriaxone † 1 or 2 grams daily (N=942) Local: Infused vein complication Systemic: 7.1 7.9 5.4

Death 2.5 1.6 1.3 1.6 Edema/swelling 3.4 2.5 2.9 3.3 Fever 5.0

6.6 2.3

Abdominal pain 3.6 4.8 4.3 3.9 Hypotension 2.0 1.4 1.0 1.2 Constipation

4.0 5.4 3.3

Diarrhea 10.3 12.1 9.2 9.8 Nausea 8.5 8.7 6.4 7.4 Vomiting 3.7

5.3 4.0

Headache 5.6 5.4 6.8 6.9 Insomnia 3.2 5.2 3.0 4.1 Dyspnea 2.6

1.8 1.0

Pruritus 2.0 2.6 1.0 1.9 Rash 2.5 3.1 2.3 1.5 Vaginitis 1.4

1.0 3.3

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. 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 , 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 gram 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 ≥2.0% of patients in this trial. Table 4 Incidence (%) of Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in ≥2.0% of Adult Patients Treated With Ertapenem for Injection for Prophylaxis of Surgical Site Infections Following Elective Colorectal Surgery Adverse Events Ertapenem for Injection 1 gram (N = 476) Cefotetan 2 grams (N = 476) Anemia 5.7

Small intestinal obstruction 2.1 1.9 Pneumonia 2.1 4.0 Postoperative infection 2.3 4.0

Urinary tract infection 3.8

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. 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 ≥2.0% 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 ≥2.0% of Pediatric Patients Treated With Ertapenem for Injection in Clinical Trials * 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 IV twice daily up to a maximum of 1 gram or ceftriaxone 50 mg/kg/day IV in two divided doses up to a maximum of 2 grams, and patients 13 to 17 years of age received ertapenem for injection 1 gram IV daily or ceftriaxone 50 mg/kg/day IV in a single daily dose. † 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 IV twice daily up to a maximum of 1 gram and patients 13 to 17 years of age received ertapenem for injection 1 gram IV daily or ticarcillin/clavulanate 50 mg/kg for patients <60 kg or ticarcillin/clavulanate 3.0 grams for patients >60 kg, 4 or 6 times a day. Adverse Events Ertapenem for Injection *,† (N=384) Ceftriaxone* (N=100) Ticarcillin/ Clavulanate † (N=24) Local: Infusion Site Erythema 3.9 3.0

Infusion Site Pain 7.0 4.0 20.8 Systemic: Abdominal Pain 4.7 3.0 4.2

Constipation 2.3 0.0

Pyrexia 4.9 6.0 8.3 Upper Respiratory Tract Infection 2.3 3.0 0.0 Headache

4.4 4.0

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.

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, encephalopathy (recovery was prolonged in patients with renal impairment) Psychiatric Disorders: altered mental status (including aggression, delirium), hallucinations Skin and Subcutaneous Tissue Disorders: Acute Generalized Exanthematous Pustulosis (AGEP), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS syndrome), hypersensitivity vasculitis

Adverse Laboratory Changes in Clinical Trials Adults Receiving Ertapenem for Injection as

Treatment Regimen Laboratory adverse experiences that were reported during therapy in ≥2.0% 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 ≥2.0% 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 (6.0%), 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* (%) of Laboratory Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in ≥2.0% of Adult Patients Treated With Ertapenem for Injection in Clinical Trials * Number of patients with laboratory adverse experiences/Number of patients with the laboratory test † 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 pelvic infections trials § Includes Phase IIb/III Community acquired pneumonia and Complicated urinary tract infections, and Phase IIa trials Adverse laboratory experiences Ertapenem for Injection ‡ 1 gram daily (n † =766) Piperacillin/ Tazobactam ‡ 3.375 grams q6h (n † =755) Ertapenem for Injection § 1 gram daily (n † =1122) Ceftriaxone § 1 or 2 grams daily (n † =920) ALT increased 8.8 7.3 8.3

AST increased 8.4 8.3 7.1 6.5 Serum alkaline phosphatase increased 6.6 7.2

4.3

Eosinophils increased 1.1 1.1 2.1 1.8 Hematocrit decreased 3.0 2.9 3.4 2.4

Hemoglobin decreased 4.9 4.7 4.5

Platelet count increased 6.5 6.3 4.3 3.5 Urine

RBCs increased 2.5 2.9 1.1

Urine

WBCs increased 2.5 3.2 1.6

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 gram 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 ≥2.0% 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 ≥2.0% 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 (3.0%), ALT increased (2.2%), and AST increased (2.1%). Table 7 Incidence* (%) of Specific Laboratory Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in ≥2.0% of Pediatric Patients Treated With Ertapenem for Injection in Clinical Trials * Number of patients with laboratory adverse experiences/Number of patients with the laboratory test; where at least 300 patients had the test † Number of patients with one or more laboratory tests Adverse laboratory experiences Ertapenem for Injection (n † =379) Ceftriaxone (n † =97) Ticarcillin/Clavulanate (n † =24) ALT Increased 3.8 1.1

AST Increased 3.8 1.1 4.3 Neutrophil Count Decreased 5.8 3.1 0.0 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.

Probenecid Probenecid interferes with the active tubular secretion of ertapenem, resulting in

increased plasma concentrations of ertapenem . Co-administration of probenecid with ertapenem is not recommended.

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 of 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. Although the mechanism of this interaction is unknown, data from in vitro and animal studies suggest that carbapenems may inhibit the hydrolysis of valproic acid's glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the serum concentrations of valproic acid.

Pregnancy Risk Summary Available data from a small number of post-marketing 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 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.

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 . 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.

Ertapenem for injection 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. Due to the use of lidocaine HCl as a diluent, ertapenem for injection administered intramuscularly is contraindicated in patients with a known hypersensitivity to local anesthetics of the amide type. Known hypersensitivity to product components or anaphylactic reactions to β-lactams.

Due to the use of lidocaine HCl as a diluent, ertapenem for injection administered intramuscularly is contraindicated in patients with a known hypersensitivity to local anesthetics of the amide type.

No specific information is available on the treatment of overdosage with ertapenem for injection. Intentional overdosing of ertapenem for injection is unlikely. Intravenous administration of ertapenem for injection at a dose of 2 grams over 30 min or 3 grams over 1 to 2h in healthy adult volunteers resulted in an increased incidence of nausea.

In clinical trials in adults, inadvertent administration of three 1 gram doses of ertapenem for injection 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 to a maximum of 2 grams did not result in toxicity. In the event of an overdose, ertapenem for injection should be discontinued and general supportive treatment given until renal elimination takes place.

Ertapenem for injection can be removed by hemodialysis; the plasma clearance of the total fraction of ertapenem was increased 30% in subjects with end-stage renal disease when hemodialysis (4 hour session) was performed immediately following administration. However, no information is available on the use of hemodialysis to treat overdosage.