Ertamac

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Ertamac® and other antibacterial drugs, Ertamac should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. W hen 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

Ertamac 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.

Complicated Intra-Abdominal Infections

Ertamac 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.

Complicated Skin And Skin Structure Infections, Including Diabetic Foot Infections Without Osteomyelitis

Ertamac 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. Ertamac has not been studied in diabetic foot infections with concomitant osteomyelitis.

Community Acquired Pneumonia

Ertamac 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.

Complicated Urinary Tract Infections Including Pyelonephritis

Ertamac is indicated for the treatment of 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

Ertamac 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

Ertamac is indicated in adults for:

Prophylaxis Of Surgical Site Infection Following Elective Colorectal Surgery

Ertamac is indicated for the prevention of surgical site infection following elective colorectal surgery.

Instructions For Use In All Patients

For Intravenous or Intramuscular Use

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

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

Treatment Regimen

13 Years Of Age And Older

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

3 Months To 12 years Of Age

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

Table 1 presents treatment guidelines for Ertamac.

Table 1 : Treatment Guidelines for Adults and Pediatric Patients With Normal Renal Function* and Body Weight

Prophylactic Regimen In Adults

Table 2 presents prophylaxis guidelines for Ertamac.

Table 2 : Prophylaxis Guidelines for Adults

Patients With Renal Impairment

Ertamac 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.

Patients On Hemodialysis

W hen adult patients on hemodialysis are given the recommended daily dose of 500 mg of Ertamac within 6 hours prior to hemodialysis, a supplementary dose of 150 mg is recommended following the hemodialysis session. If Ertamac 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 in pediatric patients on hemodialysis.

W hen only the serum creatinine is available, the following formula¹ may be used to estimate creatinine clearance. The serum creatinine should represent a steady state of renal function.

Patients With Hepatic Impairment

No dose adjustment recommendations can be made in patients with hepatic impairment.

Preparation And Reconstitution For Administration

Vials

Adults And Pediatric Patients 13 Years Of Age And Older

Preparation For Intravenous Administration

DO NOT MIX OR CO-INFUSE Ertamac W ITH OTHER MEDICATIONS. DO NOT USE DILUENTS CONTAINING DEXTROSE (α-D-GLUCOSE).

Ertamac MUST BE RECONSTITUTED AND THEN DILUTED PRIOR TO ADMINISTRATION.

1. Reconstitute the contents of a 1 g vial of Ertamac with 10 mL of one of the following: W ater for 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 0.9% Sodium Chloride Injection.
3. Complete the infusion within 6 hours of reconstitution.

Preparation for intramuscular administration:

Ertamac MUST BE RECONSTITUTED PRIOR TO ADMINISTRATION.

1. Reconstitute the contents of a 1 g vial of Ertamac with 3.2 mL of 1.0% lidocaine HCl injection² (without epinephrine). Shake vial thoroughly to form solution.
2. Immediately withdraw the contents of the vial 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.

Pediatric Patients 3 Months To 12 Years Of Age

Preparation For Intravenous Administration

DO NOT MIX OR CO-INFUSE Ertamac W ITH OTHER MEDICATIONS. DO NOT USE DILUENTS CONTAINING DEXTROSE (α-D-GLUCOSE).

Ertamac MUST BE RECONSTITUTED AND THEN DILUTED PRIOR TO ADMINISTRATION.

1. Reconstitute the contents of a 1 g vial of Ertamac with 10 mL of one of the following: W ater 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

Ertamac MUST BE RECONSTITUTED PRIOR TO ADMINISTRATION.

1. Reconstitute the contents of a 1 g vial of Ertamac 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.

ADD-Vantage® Vials

Ertamac in ADD-Vantage® vials should be reconstituted with ADD-Vantage® diluent containers containing 50 mL or 100 mL of 0.9% Sodium Chloride Injection.

Instructions For Use Of

Ertamac®
(Ertapenem for Injection) 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 W ITH SYRINGE.

Figure 1

Figure 2

To remove the vial port cover, grasp the tab on the pull ring, pull up to break the three tie strings, then pull back to remove the cover. (SEE FIGURE 3.)

Screw the vial into the vial port until it will go no further. THE VIAL MUST BE SCREWED IN TIGHTLY 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 vial is seated, do not attempt to remove. (SEE FIGURE 4.)

Recheck the vial to assure that it is tight by trying to turn it further in the direction of assembly.

Label appropriately.

Figure 3

 Figure 4

To Prepare Admixture:

Squeeze the bottom of the diluent container gently to inflate the portion of the container surrounding the end of the drug vial.

With the other hand, push the drug vial down into the container telescoping the walls of the container. Grasp the inner cap of the vial through the walls of the container. (SEE FIGURE 5.)

Pull the inner cap from the drug vial. (SEE FIGURE 6.) Verify that the rubber stopper has been pulled out, allowing the drug and diluent to mix.

Mix container contents thoroughly and use within the specified time.

Figure 5

Figure 6

Preparation for Administration: (Use Aseptic Technique)

Confirm the activation and admixture of vial contents.

Check for leaks by squeezing container firmly. If leaks are found, discard unit as sterility may be impaired. Close flow control clamp of administration set.

Remove cover from outlet port at bottom of container.

Insert piercing pin of administration set into port with a twisting motion until the pin is firmly seated.

NOTE: See full directions on administration set carton.

Lift the free end of the hanger loop on the bottom of the vial, breaking the two tie strings. Bend the loop outward to lock it in the upright position, then suspend container from hanger.

Squeeze and release drip chamber to establish proper fluid level in chamber.

Open flow control clamp and clear air from set. Close clamp.

Attach set to venipuncture device. If device is not indwelling, prime and make venipuncture.

Regulate rate of administration with flow control clamp.

WARNING: Do not use flexible container in series connections.

Storage

Ertamac (Ertapenem for Injection) 1 g single dose ADD-Vantage® vials should be prepared with ADD-Vantage® diluent containers containing 50 mL or 100 mL of 0.9% Sodium Chloride Injection. W hen prepared with this diluent, Ertamac (Ertapenem for Injection) maintains satisfactory potency for 6 hours at room temperature (25°C) or for 24 hours under refrigeration (5°C) and used within 4 hours after removal from refrigeration. Solutions of Ertamac should not be frozen.

Before administering, see accompanying package circular for Ertamac (Ertapenem for Injection). Parenteral drug products should be inspected visually for particulate matter and discoloration prior to use, whenever solution and container permit. Solutions of Ertamac range from colorless to pale yellow. Variations of color within this range do not affect the potency of the product.

• Ertamac 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, Ertamac administered intramuscularly is contraindicated in patients with a known hypersensitivity to local anesthetics of the amide type.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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 betalactam. Before initiating therapy with Ertamac, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, other beta-lactams and other allergens. If an allergic reaction to Ertamac occurs, discontinue the drug immediately. Serious anaphylactic reactions require immediate emergency treatment as clinically indicated.

Seizure Potential

Seizures and other central nervous system (CNS) adverse experiences have been reported during treatment with Ertamac. During clinical investigations in adult patients treated with Ertamac (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. 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 Ertamac re-examined to determine whether it should be decreased or discontinued.

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 Ertamac is necessary, supplemental anticonvulsant therapy should be considered.

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.

Caution With Intramuscular Administration

Caution should be taken when administering Ertamac intramuscularly to avoid inadvertent injection into a blood vessel.

Development Of Drug-Resistant Bacteria

As with other antibiotics, prolonged use of Ertamac 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 Ertamac 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.

Laboratory Tests

While Ertamac 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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No long-term studies in animals have been performed to evaluate the carcinogenic potential of ertapenem.

Ertapenem was neither mutagenic nor genotoxic in the following in vitro assays: alkaline elution/rat hepatocyte assay, chromosomal aberration assay in Chinese hamster ovary cells, and TK6 human lymphoblastoid cell mutagenesis assay; and in the in vivo mouse micronucleus assay.

In mice and rats, IV doses of up to 700 mg/kg/day (for mice, approximately 3 times the recommended human dose of 1 g based on body surface area and for rats, approximately 1.2 times the human exposure at the recommended dose of 1 g based on plasma AUCs) resulted in no effects on mating performance, fecundity, fertility, or embryonic survival.

Use In Specific Populations

Pregnancy

Pregnancy Category B

In mice and rats given intravenous doses of up to 700 mg/kg/day (for mice, approximately 3 times the recommended human dose of 1 g based on body surface area and for rats, approximately 1.2 times the human exposure at the recommended dose of 1 g based on plasma AUCs), there was no evidence of developmental toxicity as assessed by external, visceral, and skeletal examination of the fetuses. However, in mice given 700 mg/kg/day, slight decreases in average fetal weights and an associated decrease in the average number of ossified sacrocaudal vertebrae were observed. Ertapenem crosses the placental barrier in rats.

There are, however, no adequate and well-controlled trials in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Labor And Delivery

Ertamac has not been studied for use during labor and delivery.

Nursing Mothers

Ertapenem is excreted in human breast milk. Caution should be exercised when Ertamac is administered to a nursing woman. Ertamac should be administered to nursing mothers only when the expected benefit outweighs the risk.

Pediatric Use

Safety and effectiveness of Ertamac 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.

Ertamac is not recommended in infants under 3 months of age as no data are available.

Ertamac is not recommended in the treatment of meningitis in the pediatric population due to lack of sufficient CSF penetration.

Geriatric Use

Of the 1,835 patients in Phase 2b/3 trials treated with Ertamac, 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.

Patients With Renal Impairment

Dosage adjustment is necessary in patients with creatinine clearance 30 mL/min or less.

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.

The following are described in greater detail in the WARNINGS AND PRECAUTIONS section.

• Hypersensitivity Reactions
• Seizure Potential
• Interaction with Valproic Acid
• Clostridium difficile-Associated Diarrhea (CDAD)
• Caution with Intramuscular Administration
• Development of Drug-Resistant Bacteria
• Laboratory Tests

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 Ertamac as a Treatment Regimen

Clinical trials enrolled 1954 patients treated with Ertamac; 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. Ertamac 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 Ertamac, 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 Ertamac in Clinical Trials

In patients treated for complicated intra-abdominal infections, death occurred in 4.7% (15/316) of patients receiving Ertamac 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 Ertamac, 0.3% of patients treated with piperacillin/tazobactam and 0% of patients treated with ceftriaxone.

Additional adverse experiences that were reported with Ertamac 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 Ertamac, 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 Ertamac 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 Ertamac in previous clinical trials. Table 4 shows the incidence of adverse experiences other than those previously described above for Ertamac 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 Ertamac for Prophylaxis of Surgical Site Infections Following Elective Colorectal Surgery

Additional adverse experiences that were reported in this prophylaxis trial with Ertamac, 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 Ertamac as a Treatment Regimen

Clinical trials enrolled 384 patients treated with Ertamac; 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 Ertamac, 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 Ertamac in Clinical Trials

Additional adverse experiences that were reported with Ertamac 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 Ertamac. 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: Drug Rash with Eosinophilia and Systemic Symptoms (DRESS syndrome)

Adverse Laboratory Changes In Clinical Trials

Adults Receiving Ertamac as Treatment Regimen

Laboratory adverse experiences that were reported during therapy in ≥ 2.0% of adult patients treated with Ertamac 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 Ertamac, 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%). Ertamac 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 Ertamac in Clinical Trials

Additional laboratory adverse experiences that were reported during therapy in > 0.1% of patients treated with Ertamac 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, W BC, 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 Ertamac, 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 Ertamac 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 Ertamac in previous clinical trials.

Pediatric Patients Receiving Ertamac as a Treatment Regimen

Laboratory adverse experiences that were reported during therapy in ≥ 2.0% of pediatric patients treated with Ertamac 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 Ertamac, 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 Ertamac in Clinical Trials

Additional laboratory adverse experiences that were reported during therapy in > 0.5% of patients treated with Ertamac in clinical trials include: alkaline phosphatase increased, eosinophil count increased, platelet count increased, white blood cell count decreased and urine protein present.

No specific information is available on the treatment of overdosage with Ertamac. Intentional overdosing of Ertamac is unlikely. Intravenous administration of Ertamac at a dose of 2 g over 30 min or 3 g over 1-2h in healthy adult volunteers resulted in an increased incidence of nausea. In clinical trials in adults, inadvertent administration of three 1 g doses of Ertamac 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 g did not result in toxicity.

In the event of an overdose, Ertamac should be discontinued and general supportive treatment given until renal elimination takes place.

Ertamac 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.

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

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. 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 IV* Dose Administration

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 (Cmax) are achieved in approximately 2.3 hours (Tmax).

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 (Vss) 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 AUC0-24 in skin blister fluid/AUC0-24 in 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

The concentration of ertapenem in breast milk from 5 lactating women with pelvic infections (5 to 14 days postpartum) was measured at random time points daily for 5 consecutive days following the last 1 g dose of intravenous therapy (3-10 days of therapy). 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; 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.

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 0-2 hours postdose, 5.4% during 4-6 hours postdose, and 2.4% during 12-24 hours postdose.