Ertapenem

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 Intra-Abdominal Infections

  Ertapenem for Injection is indicated for the treatment of adult patients and pediatric patients (3 months of age and older) with 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

  .
  )
• •Complicated skin and skin structure infections, including diabetic foot infections without osteomyelitis. (
  1.2 Complicated Skin and Skin Structure Infections, Including Diabetic Foot Infections without Osteomyelitis

  Ertapenem for Injection is indicated for the treatment of adult patients and pediatric patients (3 months of age and older) with 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)].
  )
• •Community-acquired pneumonia. (
  1.3 Community Acquired Pneumonia

  Ertapenem for Injection is indicated for the treatment of adult patients and pediatric patients (3 months of age and older) with 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

  .
  )
• •Complicated urinary tract infections including pyelonephritis. (
  1.4 Complicated Urinary Tract Infections Including Pyelonephritis

  Ertapenem for Injection is indicated for the treatment of adult patients and pediatric patients (3 months of age and older) with complicated urinary tract infections including pyelonephritis due to

  Escherichia coli

  , including cases with concurrent bacteremia, or

  Klebsiella pneumoniae

  .
  )
• •Acute pelvic infections including postpartum endomyometritis, septic abortion and post-surgical gynecologic infections. (
  1.5 Acute Pelvic Infections Including Postpartum Endomyometritis, Septic Abortion and Post-Surgical Gynecologic Infections

  Ertapenem for Injection is indicated for the treatment of adult patients and pediatric patients (3 months of age and older) with 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

  .
  )

Ertapenem for Injection is indicated in adults for the prophylaxis of surgical site infection following elective colorectal surgery. (

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. (1.7)

Ertapenem for Injection should be infused over 30 minutes in both the Treatment and Prophylactic regimens. (

Dosing considerations should be made in adults with advanced or end-stage renal impairment and those on hemodialysis. (

Treatment regimen: 

• •Adults and pediatric patients 13 years of age and older. The dosage should be 1 gram once a day intravenously or intramuscularly. (
  2.2 Treatment Regimen

  13 years of age and older

  The dose of Ertapenem for Injection in patients 13 years of age and older is 1 gram (g) given once a day

  [see Clinical Pharmacology (12.3)].

  3 months to 12 years of age

  The dose of Ertapenem for Injection in patients 3 months to 12 years of age is 15 mg/kg twice daily (not to exceed 1 g/day).

  Table 1presents treatment guidelines for Ertapenem for Injection.

  Table 1: Treatment Guidelines for Adults and Pediatric Patients With Normal Renal Functiondefined as creatinine clearance >90 mL/min/1.73 m²and Body Weight

  Infection due to the designated pathogens [see Indications and Usage (1)]	Daily Dose (IV or IM) Adults and Pediatric Patients 13 years of age and older	Daily Dose (IV or IM) Pediatric Patients 3 months to 12 years of age	Recommended Duration of Total Antimicrobial Treatment
  Complicated intra-abdominal infections	1 g	15 mg/kg twice dailynot to exceed 1 g/day	5 to 14 days
  Complicated skin and skin structure infections, including diabetic foot infectionsErtapenem for Injection has not been studied in diabetic foot infections with concomitant osteomyelitis [see Clinical Studies (14.1)] .	1 g	15 mg/kg twice daily	7 to 14 daysadult patients with diabetic foot infections received up to 28 days of treatment (parenteral or parenteral plus oral switch therapy)
  Community acquired pneumonia	1 g	15 mg/kg twice daily	10 to 14 daysduration includes a possible switch to an appropriate oral therapy, after at least 3 days of parenteral therapy, once clinical improvement has been demonstrated.
  Complicated urinary tract infections, including pyelonephritis	1 g	15 mg/kg twice daily	10 to 14 days
  Acute pelvic infections including postpartum endomyometritis, septic abortion and post-surgical gynecologic infections	1 g	15 mg/kg twice daily	3 to 10 days
  )
• •Patients 3 months to 12 years of age should be administered 15 mg/kg twice daily (not to exceed 1 g/day intravenously or intramuscularly.) (
  2.2 Treatment Regimen

  13 years of age and older

  The dose of Ertapenem for Injection in patients 13 years of age and older is 1 gram (g) given once a day

  [see Clinical Pharmacology (12.3)].

  3 months to 12 years of age

  The dose of Ertapenem for Injection in patients 3 months to 12 years of age is 15 mg/kg twice daily (not to exceed 1 g/day).

  Table 1presents treatment guidelines for Ertapenem for Injection.

  Table 1: Treatment Guidelines for Adults and Pediatric Patients With Normal Renal Functiondefined as creatinine clearance >90 mL/min/1.73 m²and Body Weight

  Infection due to the designated pathogens [see Indications and Usage (1)]	Daily Dose (IV or IM) Adults and Pediatric Patients 13 years of age and older	Daily Dose (IV or IM) Pediatric Patients 3 months to 12 years of age	Recommended Duration of Total Antimicrobial Treatment
  Complicated intra-abdominal infections	1 g	15 mg/kg twice dailynot to exceed 1 g/day	5 to 14 days
  Complicated skin and skin structure infections, including diabetic foot infectionsErtapenem for Injection has not been studied in diabetic foot infections with concomitant osteomyelitis [see Clinical Studies (14.1)] .	1 g	15 mg/kg twice daily	7 to 14 daysadult patients with diabetic foot infections received up to 28 days of treatment (parenteral or parenteral plus oral switch therapy)
  Community acquired pneumonia	1 g	15 mg/kg twice daily	10 to 14 daysduration includes a possible switch to an appropriate oral therapy, after at least 3 days of parenteral therapy, once clinical improvement has been demonstrated.
  Complicated urinary tract infections, including pyelonephritis	1 g	15 mg/kg twice daily	10 to 14 days
  Acute pelvic infections including postpartum endomyometritis, septic abortion and post-surgical gynecologic infections	1 g	15 mg/kg twice daily	3 to 10 days
  )
• •Intravenous infusion may be administered in adults and pediatrics for up to 14 days or intramuscular injection for up to 7 days. (
  2.1 Instructions for Use in All Patients

  For Intravenous or Intramuscular Use

  DO NOT MIX OR CO-INFUSE ERTAPENEM FOR INJECTION WITH OTHER MEDICATIONS. DO NOT USE DILUENTS CONTAINING DEXTROSE (α-D-GLUCOSE).

  Ertapenem for Injection may be administered by intravenous infusion for up to 14 days or intramuscular injection for up to 7 days. When administered intravenously, Ertapenem for Injection should be infused over a period of 30 minutes. Intramuscular administration of Ertapenem for Injection may be used as an alternative to intravenous administration in the treatment of those infections for which intramuscular therapy is appropriate.
  )

Prophylaxis regimen for adults:

• •1 gram single dose given 1 hour prior to elective colorectal surgery. (
  2.3 Prophylactic Regimen in Adults

  Table 2presents prophylaxis guidelines for Ertapenem for Injection.

  Table 2: Prophylaxis Guidelines for Adults

  Indication	Daily Dose (IV) Adults	Recommended Duration of Total Antimicrobial Treatment
  Prophylaxis of surgical site infection following elective colorectal surgery	1 g	Single intravenous dose given 1 hour prior to surgical incision
  )

Ertapenem for Injection is a sterile lyophilized powder in a single-dose vial containing 1 g ertapenem equivalent to 1.046 g ertapenem sodium for intravenous infusion or for intramuscular injection after reconstitution.

• •Renal Impairment: Dose adjustment is necessary, if creatinine clearance is ≤30 mL/min/1.73 m². (
  2.4 Patients with Renal Impairment

  Ertapenem for Injection may be used for the treatment of infections in adult patients with renal impairment. In patients whose creatinine clearance is >30 mL/min/1.73 m², no dosage adjustment is necessary. Adult patients with severe renal impairment (creatinine clearance ≤30 mL/min/1.73 m²) and end-stage renal disease (creatinine clearance ≤10 mL/min/1.73 m²) should receive 500 mg daily. A supplementary dose of 150 mg is recommended if ertapenem is administered within 6 hours prior to hemodialysis. There are no data in pediatric patients with renal impairment.
  ,
  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)]

  .
  ,
  12.3 Pharmacokinetics

  Average plasma concentrations (mcg/mL) of ertapenem following a single 30-minute infusion of a 1 g intravenous (IV) dose and administration of a single 1 g intramuscular (IM) dose in healthy young adults are presented in Table 8.

  Table 8: Plasma Concentrations of Ertapenem in Adults After Single Dose Administration

  	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
  1 g IVInfused at a constant rate over 30 minutes	155	115	83	48	31	20	9	3	1
  1 g IM	33	53	67	57	40	27	13	4	2

  The area under the plasma concentration-time curve (AUC) of ertapenem in adults increased less-than dose-proportional based on total ertapenem concentrations over the 0.5 to 2 g dose range, whereas the AUC increased greater-than dose-proportional based on unbound ertapenem concentrations. Ertapenem exhibits non-linear pharmacokinetics due to concentration-dependent plasma protein binding at the proposed therapeutic dose

  [see Clinical Pharmacology (12.3)]

  . There is no accumulation of ertapenem following multiple IV or IM 1 g daily doses in healthy adults.

  Average plasma concentrations (mcg/mL) of ertapenem in pediatric patients are presented in Table 9.

  Table 9: Plasma Concentrations of Ertapenem in Pediatric Patients After Single IVInfused at a constant rate over 30 minutesDose Administration

  Age Group	Dose	Average Plasma Concentrations (mcg/mL)
  		0.5 hr	1 hr	2 hr	4 hr	6 hr	8 hr	12 hr	24 hr
  3 to 23 months	15 mg/kgup to a maximum dose of 1 g/day	103.8	57.3	43.6	23.7	13.5	8.2	2.5	-
  	20 mg/kg	126.8	87.6	58.7	28.4	-	12	3.4	0.4
  	40 mg/kgup to a maximum dose of 2 g/day	199.1	144.1	95.7	58	-	20.2	7.7	0.6
  2 to 12 years	15 mg/kg	113.2	63.9	42.1	21.9	12.8	7.6	3	-
  	20 mg/kg	147.6	97.6	63.2	34.5	-	12.3	4.9	0.5
  	40 mg/kg	241.7	152.7	96.3	55.6	-	18.8	7.2	0.6
  13 to 17 years	20 mg/kg	170.4	98.3	67.8	40.4	-	16	7	1.1
  	1 gBased on three patients receiving 1 g ertapenem who volunteered for pharmacokinetic assessment in one of the two safety and efficacy trials	155.9	110.9	74.8	-	24	-	6.2	-
  	40 mg/kg	255	188.7	127.9	76.2	-	31	15.3	2.1

  Absorption

  Ertapenem, reconstituted with 1% lidocaine HCl injection, USP (in saline without epinephrine), is almost completely absorbed following intramuscular (IM) administration at the recommended dose of 1 g. The mean bioavailability is approximately 90%. Following 1 g daily IM administration, mean peak plasma concentrations (C_max) are achieved in approximately 2.3 hours (T_max).

  Distribution

  Ertapenem is highly bound to human plasma proteins, primarily albumin. In healthy young adults, the protein binding of ertapenem decreases as plasma concentrations increase, from approximately 95% bound at an approximate plasma concentration of <100 micrograms (mcg)/mL to approximately 85% bound at an approximate plasma concentration of 300 mcg/mL.

  The apparent volume of distribution at steady state (V_ss) of ertapenem in adults is approximately 0.12 liter/kg, approximately 0.2 liter/kg in pediatric patients 3 months to 12 years of age and approximately 0.16 liter/kg in pediatric patients 13 to 17 years of age.

  The concentrations of ertapenem achieved in suction-induced skin blister fluid at each sampling point on the third day of 1 g once daily IV doses are presented in Table 10. The ratio of AUC_0-24in skin blister fluid/AUC_0-24in plasma is 0.61.

  Table 10: Concentrations (mcg/mL) of Ertapenem in Adult Skin Blister Fluid at each Sampling Point on the Third Day of 1-g Once Daily IV Doses

  0.5 hr	1 hr	2 hr	4 hr	8 hr	12 hr	24 hr
  7	12	17	24	24	21	8

  Metabolism

  In healthy young adults, after infusion of 1 g IV radiolabeled ertapenem, the plasma radioactivity consists predominantly (94%) of ertapenem. The major metabolite of ertapenem is the inactive ring-opened derivative formed by hydrolysis of the beta-lactam ring.

  Elimination

  Ertapenem is eliminated primarily by the kidneys. The mean plasma half-life in healthy young adults is approximately 4 hours and the plasma clearance is approximately 1.8 L/hour. The mean plasma half-life in pediatric patients 13 to 17 years of age is approximately 4 hours and approximately 2.5 hours in pediatric patients 3 months to 12 years of age.

  Following the administration of 1 g IV radiolabeled ertapenem to healthy young adults, approximately 80% is recovered in urine and 10% in feces. Of the 80% recovered in urine, approximately 38% is excreted as unchanged drug and approximately 37% as the ring-opened metabolite.

  In healthy young adults given a 1 g IV dose, the mean percentage of the administered dose excreted in urine was 17.4% during 0 to 2 hours postdose, 5.4% during 4 to 6 hours postdose, and 2.4% during 12 to 24 hours postdose.

  Special Populations

  Renal Impairment

  Total and unbound fractions of ertapenem pharmacokinetics were investigated in 26 adult subjects (31 to 80 years of age) with varying degrees of renal impairment. Following a single 1 g IV dose of ertapenem, the unbound AUC increased 1.5-fold and 2.3-fold in subjects with mild renal impairment (CL_CR60 to 90 mL/min/1.73 m²) and moderate renal impairment (CL_CR31 to 59 mL/min/1.73 m²), respectively, compared with healthy young subjects (25 to 45 years of age). No dosage adjustment is necessary in patients with CL_CR≥31 mL/min/1.73 m². The unbound AUC increased 4.4-fold and 7.6-fold in subjects with advanced renal impairment (CL_CR5 to 30 mL/min/1.73 m²) and end-stage renal disease (CL_CR<10 mL/min/1.73 m²), respectively, compared with healthy young subjects. The effects of renal impairment on AUC of total drug were of smaller magnitude. The recommended dose of ertapenem in adult patients with CL_CR≤30 mL/min/1.73 m²is 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, approximately 30% of the dose was recovered in the dialysate. Dose adjustments are recommended for patients with severe renal impairment and end-stage renal disease

  [see Dosage and Administration (2.4)]

  . There are no data in pediatric patients with renal impairment.

  Hepatic Impairment

  The pharmacokinetics of ertapenem in patients with hepatic impairment have not been established. However, ertapenem does not appear to undergo hepatic metabolism based on

  in vitro

  studies and approximately 10% of an administered dose is recovered in the feces

  [see Clinical Pharmacology (12.3)

  and

  Dosage and Administration (2.6)]

  .

  Gender

  The effect of gender on the pharmacokinetics of ertapenem was evaluated in healthy male (n=8) and 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

  The impact of age on the pharmacokinetics of ertapenem was evaluated in healthy male (n=7) and healthy female (n=7) subjects ≥65 years of age. The total and unbound AUC increased 37% and 67%, respectively, in elderly adults relative to young adults. These changes were attributed to age-related changes in creatinine clearance. No dosage adjustment is necessary for elderly patients with normal (for their age) renal function.

  Pediatric Patients

  Plasma concentrations of ertapenem are comparable in pediatric patients 13 to 17 years of age and adults following a 1 g once daily IV dose.

  Following the 20 mg/kg dose (up to a maximum dose of 1 g), the pharmacokinetic parameter values in patients 13 to 17 years of age (N=6) were generally comparable to those in healthy young adults.

  Plasma concentrations at the midpoint of the dosing interval following a single 15 mg/kg IV dose of ertapenem in patients 3 months to 12 years of age are comparable to plasma concentrations at the midpoint of the dosing interval following a 1 g once daily IV dose in adults

  [see Clinical Pharmacology (12.3)]

  . The plasma clearance (mL/min/kg) of ertapenem in patients 3 months to 12 years of age is approximately 2-fold higher as compared to that in adults. At the 15 mg/kg dose, the AUC value (doubled to model a twice daily dosing regimen, i.e., 30 mg/kg/day exposure) in patients 3 months to 12 years of age was comparable to the AUC value in young healthy adults receiving a 1 g IV dose of ertapenem.

  Drug Interactions

  When ertapenem is co-administered with probenecid (500 mg p.o. every 6 hours), probenecid competes for active tubular secretion and reduces the renal clearance of ertapenem. Based on total ertapenem concentrations, probenecid increased the AUC of ertapenem by 25%, and reduced the plasma and renal clearance of ertapenem by 20% and 35%, respectively. The half-life of ertapenem was increased from 4 to 4.8 hours.

  In vitro

  studies in human liver microsomes indicate that ertapenem does not inhibit metabolism mediated by any of the following cytochrome p450 (CYP) isoforms: 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4.

  In vitro

  studies indicate that ertapenem does not inhibit P-glycoprotein-mediated transport of digoxin or vinblastine and that ertapenem is not a substrate for P-glycoprotein-mediated transport.
  )

• •Serious hypersensitivity (anaphylactic) reactions have been reported in patients receiving β-lactams. (
  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.
  )
• •Seizures and other central nervous system adverse experiences have been reported during treatment. (
  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.
  )
• •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 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)]

  .
  )
• •
  Clostridioides difficile
  -associated diarrhea (ranging from mild diarrhea to fatal colitis): Evaluate if diarrhea occurs. (
  5.4

  Clostridioides 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

  Clostridioides difficile

  .

  Clostridioides difficile

  produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of

  Clostridioides 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

  Clostridioides difficile

  may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of

  Clostridioides difficile

  , and surgical evaluation should be instituted as clinically indicated.
  )
• •Caution should be taken when administering ertapenem for injection intramuscularly to avoid inadvertent injection into a blood vessel. (
  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)]

  .
  )