Imipenem and Cilastatin

11 DESCRIPTION Imipenem and Cilastatin for Injection, USP is a sterile formulation of imipenem, a penem antibacterial, and cilastatin, a renal dehydropeptidase inhibitor with sodium bicarbonate added as a buffer. Imipenem and Cilastatin for Injection, USP is an antibacterial drug for intravenous administration. Imipenem (N-formimidoylthienamycin monohydrate) is a crystalline derivative of thienamycin, which is produced by Streptomyces cattleya . Its chemical name is (5 R ,6 S )-3-[[2-(formimidoylamino)ethyl]thio]-6-[( R )-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monohydrate. It is an off-white, nonhygroscopic crystalline compound with a molecular weight of 317.37. It is sparingly soluble in water and slightly soluble in methanol. Its empirical formula is C 12 H 17 N 3 O 4 S∙H 2 O, and its structural formula is: Cilastatin sodium is the sodium salt of a derivatized heptenoic acid. Its chemical name is sodium ( Z )-7[[( R )-2-amino-2-carboxyethyl]thio]-2-[( S )-2,2-dimethylcyclopropanecarboxamido]-2-heptenoate. It is an off-white to yellowish-white, hygroscopic, amorphous compound with a molecular weight of 380.43. It is very soluble in water and in methanol. Its empirical formula is C 16 H 25 N 2 O 5 SNa, and its structural formula is: Each single-dose vial of Imipenem and Cilastatin for Injection, USP contains 500 mg imipenem (equivalent to 530 mg imipenem monohydrate), 500 mg cilastatin (equivalent to 531 mg cilastatin sodium), and 20 mg sodium bicarbonate (used as a buffer). Imipenem and Cilastatin for Injection, USP is buffered to provide solutions in the pH range of 6.5 to 8.5. There is no significant change in pH when solutions are prepared and used as directed [see How Supplied/ Storage and Handling (16.1) ]. Imipenem and Cilastatin for Injection, USP 500 mg/500 mg vial contains 37.5 mg of sodium (1.6 mEq). Solutions of Imipenem and Cilastatin for Injection, USP range from colorless to yellow. Variations of color within this range do not affect the potency of the product. Chemical Structure Chemical Structure

1 INDICATIONS AND USAGE Imipenem and Cilastatin for Injection, USP for intravenous use is a combination of imipenem, a penem antibacterial, and cilastatin, a renal dehydropeptidase inhibitor, indicated for the treatment of the following serious infections caused by designated susceptible bacteria: • Lower respiratory tract infections. ( 1.1 ) • Urinary tract infections. ( 1.2 ) • Intra-abdominal infections. ( 1.3 ) • Gynecologic infections. ( 1.4 ) • Bacterial septicemia. ( 1.5 ) • Bone and joint infections. ( 1.6 ) • Skin and skin structure infections. ( 1.7 ) • Endocarditis. ( 1.8 ) Limitations of Use: • Imipenem and Cilastatin for Injection, USP is not indicated in patients with meningitis because safety and efficacy have not been established ( 1.9 ). • Imipenem and Cilastatin for Injection, USP is not recommended in pediatric patients with CNS infections because of the risk of seizures ( 1.9 ). • Imipenem and Cilastatin for Injection, USP is not recommended in pediatric patients weighing less than 30 kg with impaired renal function ( 1.9 ). Usage: To reduce the development of drug resistant bacteria and maintain the effectiveness of Imipenem and Cilastatin for Injection, USP and other antibacterial drugs, Imipenem and Cilastatin for Injection, USP should be used only to treat infections that are proven or strongly suspected to be caused by bacteria ( 1.10 ). 1.1 Lower Respiratory Tract Infections Imipenem and Cilastatin for Injection, USP for intravenous use is indicated for the treatment of lower respiratory tract infections caused by susceptible strains of Staphylococcus aureus (penicillinase-producing isolates), Acinetobacter species, Enterobacter species, Escherichia coli , Haemophilus influenzae , Haemophilus parainfluenzae , Klebsiella species, Serratia marcescens. 1.2 Urinary Tract Infections (complicated and uncomplicated) Imipenem and Cilastatin for Injection, USP is indicated for the treatment of urinary tract infections (complicated and uncomplicated) caused by susceptible strains of Enterococcus faecalis , Staphylococcus aureus (penicillinase-producing isolates), Enterobacter species, Escherichia coli , Klebsiella species, Morganella morganii , Proteus vulgaris , Providencia rettgeri , Pseudomonas aeruginosa. 1.3 Intra-Abdominal Infections Imipenem and Cilastatin for Injection, USP is indicated for the treatment of intra-abdominal infections caused by susceptible strains of Enterococcus faecalis , Staphylococcus aureus (penicillinase-producing isolates), Staphylococcus epidermidis , Citrobacter species, Enterobacter species, Escherichia coli , Klebsiella species, Morganella morganii , Proteus species, Pseudomonas aeruginosa , Bifidobacterium species, Clostridium species, Eubacterium species, Peptococcus species, Peptostreptococcus species, Propionibacterium species, Bacteroides species including B. fragilis , Fusobacterium species . 1.4 Gynecologic Infections Imipenem and Cilastatin for Injection, USP is indicated for the treatment of gynecologic infections caused by susceptible strains of Enterococcus faecalis , Staphylococcus aureus (penicillinase-producing isolates), Staphylococcus epidermidis , Streptococcus agalactiae (Group B streptococci), Enterobacter species, Escherichia coli , Gardnerella vaginalis , Klebsiella species, Proteus species, Bifidobacterium species, Peptococcus species, Peptostreptococcus species, Propionibacterium species, Bacteroides species including B. fragilis. 1.5 Bacterial Septicemia Imipenem and Cilastatin for Injection, USP is indicated for the treatment of bacterial septicemia caused by susceptible strains of Enterococcus faecalis , Staphylococcus aureus (penicillinase-producing isolates), Enterobacter species, Escherichia coli , Klebsiella species, Pseudomonas aeruginosa , Serratia species, Bacteroides species including B. fragilis. 1.6 Bone and Joint Infections Imipenem and Cilastatin for Injection, USP is indicated for the treatment of bone and joint infections caused by susceptible strains of Enterococcus faecalis , Staphylococcus aureus (penicillinase-producing isolates), Staphylococcus epidermidis , Enterobacter species, Pseudomonas aeruginosa. 1.7 Skin and Skin Structure Infections Imipenem and Cilastatin for Injection, USP is indicated for the treatment of skin and skin structure infections caused by susceptible strains of Enterococcus faecalis , Staphylococcus aureus (penicillinase-producing isolates), Staphylococcus epidermidis , Acinetobacter species, Citrobacter species, Enterobacter species, Escherichia coli , Klebsiella species, Morganella morganii , Proteus vulgaris , Providencia rettgeri , Pseudomonas aeruginosa , Serratia species, Peptococcus species, Peptostreptococcus species, Bacteroides species including B. fragilis , Fusobacterium species . 1.8 Endocarditis Imipenem and Cilastatin for Injection, USP is indicated for the treatment of endocarditis caused by susceptible strains of Staphylococcus aureus (penicillinase-producing isolates). 1.9 Limitations of Use • Imipenem and Cilastatin for Injection, USP is not indicated in patients with meningitis because safety and efficacy have not been established. • Imipenem and Cilastatin for Injection, USP is not recommended in pediatric patients with CNS infections because of the risk of seizures [see Dosage and Administration (2.2) , Warnings and Precautions (5.2) , and Use in Specific Populations (8.4)]. • Imipenem and Cilastatin for Injection, USP is not recommended in pediatric patients less than 30 kg with impaired renal function, as no data are available [see Use in Specific Populations (8.4), and Dosage and Administration (2.2) ]. • Periodic assessment of organ system functions, including renal, hepatic and hematopoietic, is advisable during prolonged therapy. 1.10 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of Imipenem and Cilastatin for Injection, USP and other antibacterial drugs, Imipenem and Cilastatin for Injection, USP should be used only to treat 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.

5 WARNINGS AND PRECAUTIONS • Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with beta-lactams. If an allergic reaction to imipenem and cilastatin for injection occurs, discontinue the drug immediately ( 5.1 ). • Seizure Potential: Seizures and other CNS adverse reactions, such as confusional states and myoclonic activity, have been reported during treatment with imipenem and cilastatin for injection. If focal tremors, myoclonus, or seizures occur, patients should be evaluated neurologically, placed on anticonvulsant therapy if not already instituted, and the dosage of imipenem and cilastatin for injection re-examined to determine whether it should be decreased, or the antibacterial drug discontinued ( 5.2 ). • Increased Seizure Potential Due to Interaction with Valproic Acid: Co-administration of imipenem and cilastatin for injection, 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. The concomitant use of imipenem and cilastatin for injection and valproic acid/divalproex sodium is generally not recommended ( 5.3 , 7.3 ). • Clostridioides difficile-Associated Diarrhea (CDAD): has been reported with use of imipenem and cilastatin for injection and may range in severity from mild diarrhea to fatal colitis. Evaluate if diarrhea occurs ( 5.4 ). 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 imipenem and cilastatin 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 imipenem and cilastatin for injection occurs, discontinue the drug immediately. Serious anaphylactic reactions require immediate emergency treatment as clinically indicated. 5.2 Seizure Potential Seizures and other CNS adverse experiences, such as confusional states and myoclonic activity, have been reported during treatment with imipenem and cilastatin for injection, especially when recommended dosages were exceeded [see Adverse Reactions (6.1 , 6.2 )]. These experiences have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) and/or compromised renal function [see Use in Specific Populations (8.6)] . However, there have been reports of CNS adverse experiences in patients who had no recognized or documented underlying CNS disorder or compromised renal function. 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 imipenem and cilastatin for injection re-examined to determine whether it should be decreased, or the antibacterial drug discontinued. 5.3 Increased Seizure Potential Due to Interaction with Valproic Acid Case reports in the literature have shown that co-administration of carbapenems, including imipenem and cilastatin for injection, 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 imipenem and cilastatin for injection and valproic acid/divalproex sodium is generally not recommended. Antibacterials 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 imipenem and cilastatin for injection is necessary, supplemental anti-convulsant therapy should be considered [see Drug Interactions (7.3) ]. Close adherence to the recommended dosage and dosage schedules is urged, especially in patients with known factors that predispose to convulsive activity. 5.4 Clostridioides difficile -Associated Diarrhea (CDAD) Clostridioides difficile -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including imipenem and cilastatin for injection, 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 C. difficile . C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. 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 antibacterial drug 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 antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. 5.5 Development of Drug-Resistant Bacteria As with other antibacterial drugs, prolonged use of imipenem and cilastatin for injection may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the patient’s condition is essential. If superinfection occurs during therapy, appropriate measures should be taken. Prescribing imipenem and cilastatin 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.

6 ADVERSE REACTIONS The following serious adverse reactions 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) ] • Increased Seizure Potential Due to Interaction with Valproic Acid [see Warnings and Precautions (5.3) ] • Clostridioides difficile -Associated Diarrhea (CDAD) [see Warnings and Precautions (5.4) ] • Development of Drug-Resistant Bacteria [see Warnings and Precautions (5.5) ] • The most frequently occurring adverse reactions (≥ 0.2%) in adults were phlebitis, nausea, diarrhea, vomiting, rash, pain injection site, fever, hypotension, seizures, erythema at injection site, dizziness, pruritus, vein induration, urticaria, somnolence ( 6.1 ). • The most frequently occurring adverse reactions (>1%) in pediatric patients greater than or equal to 3 months of age were diarrhea, rash, phlebitis, gastroenteritis, vomiting, IV site irritation, urine discoloration ( 6.1 ). • The most frequently occurring adverse reactions (>1%) in neonates to 3 months of age were convulsions, diarrhea, oliguria/anuria, oral candidiasis, rash, tachycardia ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact WG Critical Care, LLC at 1-866-562-4708 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. Adult Patients During clinical investigations 1,723 patients were treated with imipenem and cilastatin for injection. Table 4 shows the incidence of adverse reactions reported during the clinical investigations of adult patients treated with imipenem and cilastatin for injection. Table 4: Incidence (%) Adverse reactions with an incidence ≥ 0.2% of imipenem and cilastatin for injection-treated adult patients. of Adverse Reactions Reported During Clinical Investigations of Adult Patients Treated with Imipenem and Cilastatin for Injection Body System Adverse Reactions Frequency (%) Local Administration site Phlebitis/thrombophlebitis 3.1% Pain at the injection site 0.7% Erythema at the injection site 0.4% Vein induration 0.2% Gastrointestinal Nausea 2% Diarrhea 1.8% Vomiting 1.5% Skin Rash 0.9% Pruritus 0.3% Urticaria 0.2% Vascular Hypotension 0.4% Body as a Whole Fever 0.5% Nervous system Seizures 0.4% Dizziness 0.3% Somnolence 0.2% Additional adverse reactions reported in less than 0.2% of the patients or reported since the drug was marketed are listed within each body system in order of decreasing severity (see Table 5 ). Table 5: Additional Adverse Reactions Occurring in Less than 0.2% of Adult Patients Listed within Each Body System in Order of Decreasing Severity Body System Adverse Reactions Gastrointestinal Pseudomembranous Colitis (the onset of Pseudomembranous colitis symptoms), Hemorrhagic Colitis Gastroenteritis Abdominal Pain Glossitis Tongue Papillar Hypertrophy Heartburn Pharyngeal Pain Increased Salivation CNS Encephalopathy Confusion Myoclonus Paresthesia Vertigo Headache Special Senses Hearing Loss Tinnitus Respiratory Chest Discomfort Dyspnea Hyperventilation Thoracic Spine Pain Cardiovascular Palpitations Tachycardia Skin Erythema Multiforme Angioneurotic Edema Flushing Cyanosis Hyperhidrosis Skin Texture Changes Candidiasis Pruritus Vulvae Local Administration site Infused vein infection Body as a Whole Polyarthralgia Asthenia/Weakness Renal Oliguria/Anuria Polyuria Adverse Laboratory Changes The following adverse laboratory changes were reported during clinical trials: Hepatic: Increased alanine aminotransferase (ALT or SGPT), aspartate aminotransferase (AST or SGOT), alkaline phosphatase, bilirubin, and lactate dehydrogenase (LDH) Hemic: Increased eosinophils, positive Coombs test, increased WBC, increased platelets, decreased hemoglobin and hematocrit, increased monocytes, abnormal prothrombin time, increased lymphocytes, increased basophils Electrolytes: Decreased serum sodium, increased potassium, increased chloride Renal: Increased BUN, creatinine Urinalysis: Presence of urine protein, urine red blood cells, urine white blood cells, urine casts, urine bilirubin, and urine urobilinogen. Pediatric Patients Table 6: Incidence (%) Adverse reactions that occurred in >1 % of imipenem and cilastatin for injection-treated pediatric patients (greater than or equal to 3 months of age). of Adverse Reactions Reported During Clinical Investigations of Pediatric Patients Greater Than or Equal to 3 Months of Age Treated with Imipenem and Cilastatin for Injection Body System Adverse Reactions Frequency (%) Local Administration Site Phlebitis 2.2% Intravenous Site Irritation 1.1% Gastrointestinal Diarrhea 3.9% Gastroenteritis 1.1% Vomiting 1.1% Skin Rash 2.2% Renal Urine Discoloration 1.1% Table 7: Incidence (%) Adverse reactions that occurred in >1 % of imipenem and cilastatin for injection-treated pediatric patients (neonates to 3 months of age) of Adverse Reactions Reported During Clinical Investigations of Pediatric Patients Neonates to 3 Months of Age Treated with Imipenem and Cilastatin for Injection Body System Adverse Reactions Frequency (%) Gastrointestinal Diarrhea 3% CNS Convulsions 5.9% Cardiovascular Tachycardia 1.5% Skin Rash 1.5% Body as a Whole Oral Candidiasis 1.5% Renal Oliguria/Anuria 2.2% Adverse Laboratory Changes The following adverse laboratory changes were reported in studies of 178 pediatric patients 3 months of age: increased AST (SGOT), decreased hemoglobin/hematocrit, increased platelets, increased eosinophils, increased ALT (SGPT), increased urine protein, decreased neutrophils. The following adverse laboratory changes were reported in studies of 135 patients (neonates to 3 months of age): increased eosinophils, increased AST (SGPT), increased serum creatinine, increased/decreased platelet count, increased/decreased bilirubin, increased ALT (SGPT), increased alkaline phosphatase, increased/decreased hematocrit. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of imipenem and cilastatin 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. Table 8: Adverse Reactions Identified During Post Approval Use of Imipenem and Cilastatin for Injection Body System Adverse Reactions Gastrointestinal Hepatitis (including fulminant hepatitis) Hepatic failure Jaundice Staining of the teeth and/or tongue Hematologic Pancytopenia Bone marrow depression Thrombocytopenia Neutropenia Leukopenia Hemolytic anemia CNS Tremor Psychic disturbances including hallucinations Dyskinesia Agitation Special Senses Taste perversion Skin Stevens-Johnson syndrome Toxic epidermal necrolysis Body as a whole Drug fever Renal Acute renal failure Urine discoloration Adverse Laboratory Changes Adverse laboratory changes reported since the drug was marketed were: Hematologic: agranulocytosis. Examination of published literature and spontaneous adverse reactions reports suggested a similar spectrum of adverse reactions in adult and pediatric patients.

7 DRUG INTERACTIONS • Ganciclovir: Generalized seizures have been reported in patients who received ganciclovir. Do not co-administer unless benefit outweighs risk ( 7.1 ). • Probenecid: Concomitant administration of imipenem and cilastatin for injection and probenecid results in increases in the plasma level and half-life of imipenem. Concomitant administration is not recommended ( 7.2 ). • Valproic acid/divalproex sodium: Concomitant use with imipenem and cilastatin for injection is generally not recommended. Consider other antibacterial drugs to treat infections in patients whose seizures are well-controlled on valproic acid or divalproex sodium ( 5.3 , 7.3 ). 7.1 Ganciclovir Generalized seizures have been reported in patients who received ganciclovir and imipenem and cilastatin for injection. These drugs should not be used concomitantly with imipenem and cilastatin for injection unless the potential benefits outweigh the risks. 7.2 Probenecid Concomitant administration of imipenem and cilastatin for injection and probenecid results in increases in the plasma level and half-life of imipenem. Therefore, it is not recommended that probenecid be given concomitantly with imipenem and cilastatin for injection. 7.3 Valproic Acid Case reports in the literature have shown that co-administration of carbapenems, including imipenem and cilastatin for injection, 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. 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 [see Warnings and Precautions (5.3) ]. The concomitant use of imipenem and cilastatin for injection and valproic acid/divalproex sodium is generally not recommended. Antibacterials other than carbapenems should be considered to treat infections in patients whose seizures are well-controlled on valproic acid or divalproex sodium.

8 USE IN SPECIFIC POPULATIONS • Renal Impairment: Dosage adjustment is necessary in patients with renal impairment ( 2.3 ). o Adult patients with creatinine clearances of less than or equal to 30 mL/min, whether or not undergoing hemodialysis, had a higher risk of seizure activity than those without impairment of renal function ( 5.2 ). o Therefore, close adherence to the dosing guidelines and regular monitoring of creatinine clearance for these patients is recommended (8.6). 8.1 Pregnancy Risk Summary Available data from a small number of postmarketing cases with imipenem and cilastatin for injection use in pregnancy are not sufficient to identify any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. Developmental toxicity studies with imipenem and cilastatin sodium (alone or in combination) administered to mice, rats, rabbits, and monkeys at doses 0.4 to 2.9 times the recommended human dose (RHD), (based on body surface area), showed no drug-induced fetal malformations. Embryofetal development studies with imipenem/cilastatin administered to cynomolgus monkeys at doses similar to the RHD (based on body surface area) showed an increase in embryonic loss (see Data) . The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risk of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies within the general population. Data Animal Data Reproductive toxicity studies with imipenem and cilastatin (alone or in combination) administered to mice, rats, and rabbits showed no evidence of effects on embryofetal (mice, rats and rabbits) or pre/postnatal (rats) development. Imipenem was administered intravenously to rats (gestation days (GD) 7 to 17) and rabbits (GD 6 to 18) at doses up to 900 and 60 mg/kg/day, respectively, approximately 2.9 and 0.4 times the RHD (based on body surface area). Cilastatin was administered subcutaneously to rats (GD 6 to 17) and intravenously to rabbits (GD 6 to 18) at doses up to 1000 and 300 mg/kg/day, respectively, approximately 3.2 and 1.9 times the RHD (based on body surface area). Imipenem/cilastatin was administered intravenously to mice at doses up to 320 mg/kg/day (GD 6 to 15). In two separate studies, imipenem/cilastatin was administered to rats (GD 6 to 17 and GD 15 to day 21 postpartum) both intravenously at doses up to 80 mg/kg/day and subcutaneously at 320 mg/kg/day. The higher dose is approximately equal to the RHD (based on body surface area). Imipenem/cilastatin administered intravenously to pregnant cynomolgus monkeys during organogenesis at 100 mg/kg/day, approximately 0.6 times the RHD (based on body surface area), at an infusion rate mimicking human clinical use, was not associated with fetal malformations, but there was an increase in embryonic loss relative to controls. Imipenem/cilastatin administered to pregnant cynomolgus monkeys during organogenesis at 40 mg/kg/day by bolus intravenous injection caused significant maternal toxicity including death and embryofetal loss. 8.2 Lactation Risk Summary There are insufficient data on the presence of imipenem/cilastatin in human milk, and no data on the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for imipenem and cilastatin for injection and any potential adverse effects on the breastfed child from imipenem and cilastatin for injection or from the underlying maternal condition. 8.4 Pediatric Use Use of imipenem and cilastatin for injection in pediatric patients is supported by evidence from adequate and well-controlled trials of imipenem and cilastatin for injection in adults and clinical studies in pediatric patients [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)] . Imipenem and cilastatin for injection is not recommended in pediatric patients with CNS infections because of the risk of seizures. Imipenem and cilastatin for injection is not recommended in pediatric patients less than 30 kg with renal impairment, as no data are available. 8.5 Geriatric Use Of the approximately 3600 subjects ≥18 years of age in clinical studies of imipenem and cilastatin for injection, including postmarketing studies, approximately 2800 received imipenem and cilastatin for injection. Of the subjects who received imipenem and cilastatin for injection, data are available on approximately 800 subjects who were 65 and over, including approximately 300 subjects who were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. 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. No dosage adjustment is required based on age [see Clinical Pharmacology (12.3)] . Dosage adjustment in the case of renal impairment is necessary [see Dosage and Administration (2.3) ]. 8.6 Renal Impairment Dosage adjustment is necessary in patients with renal impairment [see Dosage and Administration (2.3) ] . Adult patients with creatinine clearances of less than or equal to 30 mL/min, whether or not undergoing hemodialysis, had a higher risk of seizure activity than those without impairment of renal function [see Warnings and Precautions (5.2) ] . Therefore, close adherence to the dosing guidelines and regular monitoring of creatinine clearance for these patients is recommended.

8.1 Pregnancy Risk Summary Available data from a small number of postmarketing cases with imipenem and cilastatin for injection use in pregnancy are not sufficient to identify any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. Developmental toxicity studies with imipenem and cilastatin sodium (alone or in combination) administered to mice, rats, rabbits, and monkeys at doses 0.4 to 2.9 times the recommended human dose (RHD), (based on body surface area), showed no drug-induced fetal malformations. Embryofetal development studies with imipenem/cilastatin administered to cynomolgus monkeys at doses similar to the RHD (based on body surface area) showed an increase in embryonic loss (see Data) . The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risk of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies within the general population. Data Animal Data Reproductive toxicity studies with imipenem and cilastatin (alone or in combination) administered to mice, rats, and rabbits showed no evidence of effects on embryofetal (mice, rats and rabbits) or pre/postnatal (rats) development. Imipenem was administered intravenously to rats (gestation days (GD) 7 to 17) and rabbits (GD 6 to 18) at doses up to 900 and 60 mg/kg/day, respectively, approximately 2.9 and 0.4 times the RHD (based on body surface area). Cilastatin was administered subcutaneously to rats (GD 6 to 17) and intravenously to rabbits (GD 6 to 18) at doses up to 1000 and 300 mg/kg/day, respectively, approximately 3.2 and 1.9 times the RHD (based on body surface area). Imipenem/cilastatin was administered intravenously to mice at doses up to 320 mg/kg/day (GD 6 to 15). In two separate studies, imipenem/cilastatin was administered to rats (GD 6 to 17 and GD 15 to day 21 postpartum) both intravenously at doses up to 80 mg/kg/day and subcutaneously at 320 mg/kg/day. The higher dose is approximately equal to the RHD (based on body surface area). Imipenem/cilastatin administered intravenously to pregnant cynomolgus monkeys during organogenesis at 100 mg/kg/day, approximately 0.6 times the RHD (based on body surface area), at an infusion rate mimicking human clinical use, was not associated with fetal malformations, but there was an increase in embryonic loss relative to controls. Imipenem/cilastatin administered to pregnant cynomolgus monkeys during organogenesis at 40 mg/kg/day by bolus intravenous injection caused significant maternal toxicity including death and embryofetal loss.