Prescription Drugs

CLINICAL PHARMACOLOGY Adults Intravenous Administration Intravenous infusion of PRIMAXIN I.V. over 20 minutes results in peak plasma levels of imipenem antimicrobial activity that range from 14 to 24 μg/mL for the 250 mg dose, from 21 to 58 μg/mL for the 500 mg dose, and from 41 to 83 μg/mL for the 1000 mg dose. At these doses, plasma levels of imipenem antimicrobial activity decline to below 1 μg/mL or less in 4 to 6 hours. Peak plasma levels of cilastatin following a 20-minute intravenous infusion of PRIMAXIN I.V. range from 15 to 25 μg/mL for the 250 mg dose, from 31 to 49 μg/mL for the 500 mg dose, and from 56 to 88 μg/mL for the 1000 mg dose. The plasma half-life of each component is approximately 1 hour. The binding of imipenem to human serum proteins is approximately 20% and that of cilastatin is approximately 40%. Approximately 70% of the administered imipenem is recovered in the urine within 10 hours after which no further urinary excretion is detectable. Urine concentrations of imipenem in excess of 10 μg/mL can be maintained for up to 8 hours with PRIMAXIN I.V. at the 500-mg dose. Approximately 70% of the cilastatin sodium dose is recovered in the urine within 10 hours of administration of PRIMAXIN I.V. No accumulation of imipenem/cilastatin in plasma or urine is observed with regimens administered as frequently as every 6 hours in patients with normal renal function. In healthy elderly volunteers (65 to 75 years of age with normal renal function for their age), the pharmacokinetics of a single dose of imipenem 500 mg and cilastatin 500 mg administered intravenously over 20 minutes are consistent with those expected in subjects with slight renal impairment for which no dosage alteration is considered necessary. The mean plasma half-lives of imipenem and cilastatin are 91 ± 7.0 minutes and 69 ± 15 minutes, respectively. Multiple dosing has no effect on the pharmacokinetics of either imipenem or cilastatin, and no accumulation of imipenem/cilastatin is observed. Imipenem, when administered alone, is metabolized in the kidneys by dehydropeptidase I resulting in relatively low levels in urine. Cilastatin sodium, an inhibitor of this enzyme, effectively prevents renal metabolism of imipenem so that when imipenem and cilastatin sodium are given concomitantly, fully adequate antibacterial levels of imipenem are achieved in the urine. After a 1 gram dose of PRIMAXIN I.V., the following average levels of imipenem were measured (usually at 1 hour post dose except where indicated) in the tissues and fluids listed: Tissue or Fluid N Imipenem Level μg/mL or μg/g Range Vitreous Humor 3 3.4 (3.5 hours post dose) 2.88-3.6 Aqueous Humor 5 2.99 (2 hours post dose) 2.4-3.9 Lung Tissue 8 5.6 (median) 3.5-15.5 Sputum 1 2.1 — Pleural 1 22.0 — Peritoneal 12 23.9 S.D.+5.3 (2 hours post dose) — Bile 2 5.3 (2.25 hours post dose) 4.6-6.0 CSF (uninflamed) 5 1.0 (4 hours post dose) 0.26-2.0 CSF (inflamed) 7 2.6 (2 hours post dose) 0.5-5.5 Fallopian Tubes 1 13.6 — Endometrium 1 11.1 — Myometrium 1 5.0 — Bone 10 2.6 0.4-5.4 Interstitial Fluid 12 16.4 10.0-22.6 Skin 12 4.4 NA Fascia 12 4.4 NA Imipenem-cilastatin sodium is hemodialyzable. However, usefulness of this procedure in the overdosage setting is questionable. (See OVERDOSAGE.) Microbiology The bactericidal activity of imipenem results from the inhibition of cell wall synthesis. Its greatest affinity is for penicillin binding proteins (PBPs) 1A, 1B, 2, 4, 5 and 6 of Escherichia coli, and 1A, 1B, 2, 4 and 5 of Pseudomonas aeruginosa. The lethal effect is related to binding to PBP 2 and PBP 1B. Imipenem has a high degree of stability in the presence of beta-lactamases, both penicillinases and cephalosporinases produced by gram-negative and gram-positive bacteria. It is a potent inhibitor of betalactamases from certain gram-negative bacteria which are inherently resistant to most beta-lactam antibiotics, e.g., Pseudomonas aeruginosa, Serratia spp., and Enterobacter spp. Imipenem has in vitro activity against a wide range of gram-positive and gram-negative organisms. Imipenem has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections treated with the intravenous formulation of imipenem-cilastatin sodium as described in the INDICATIONS AND USAGE section. Gram-positive Aerobes Enterococcus faecalis (formerly S. faecalis) (NOTE: Imipenem is inactive in vitro against Enterococcus faecium [formerly S. faecium].) Staphylococcus aureus including penicillinase-producing strains Staphylococcus epidermidis including penicillinase-producing strains (NOTE: Methicillin-resistant staphylococci should be reported as resistant to imipenem.) Streptococcus agalactiae (Group B streptococci) Streptococcus pneumoniae Streptococcus pyogenes Gram-negative Aerobes Acinetobacter spp. Citrobacter spp. Enterobacter spp. Escherichia coli Gardnerella vaginalis Haemophilus influenzae Haemophilus parainfluenzae Klebsiella spp. Morganella morganii Proteus vulgaris Providencia rettgeri Pseudomonas aeruginosa (NOTE: Imipenem is inactive in vitro against Stenotrophomonas [formerly Xanthomonas, formerly Pseudomonas] maltophilia and some strains of Burkholderia cepacia.) Serratia spp., including S. marcescens Gram-positive Anaerobes Bifidobacterium spp. Clostridium spp. Eubacterium spp. Peptococcus spp. Peptostreptococcus spp. Propionibacterium spp. Gram-negative Anaerobes Bacteroides spp., including B. fragilis Fusobacterium spp. The following in vitro data are available, but their clinical significance is unknown. Imipenem exhibits in vitro minimum inhibitory concentrations (MICs) of 4 μg/mL or less against most ( ≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of imipenem in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials. Gram-positive Aerobes Bacillus spp. Listeria monocytogenes Nocardia spp. Staphylococcus saprophyticus Group C streptococci Group G streptococci Viridans group streptococci Gram-negative Aerobes Aeromonas hydrophila Alcaligenes spp. Capnocytophaga spp. Haemophilus ducreyi Neisseria gonorrhoeae including penicillinase-producing strains Pasteurella spp. Providencia stuartii Gram-negative Anaerobes Prevotella bivia Prevotella disiens Prevotella melaninogenica Veillonella spp. In vitro tests show imipenem to act synergistically with aminoglycoside antibiotics against some isolates of Pseudomonas aeruginosa. Susceptibility Test Methods When available, the clinical microbiology laboratory should provide to the physician the results of in vitro susceptibility tests for antimicrobial drug products used in resident hospitals as periodic reports which describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial. Dilution Techniques Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a broth dilution method1,2 or equivalent with standardized inoculum concentrations and standardized concentrations of imipenem powder. The MIC values should be interpreted according to criteria provided in Table 1. Diffusion Techniques Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure requires the use of standardized inoculum concentrations2,3. This procedure uses paper disks impregnated with 10-μg imipenem to test the susceptibility of microorganisms to imipenem. The disk diffusion interpretive criteria should be interpreted according to criteria provided in Table 1. Anaerobic Techniques For anaerobic bacteria, the susceptibility to imipenem as MICs can be determined by standardized test methods.2,4 The MIC values obtained should be interpreted according to criteria provided in Table 1. The MIC and disk diffusion values obtained should be interpreted according to the following criteria: Table 1: Susceptibility Interpretive Criteria for Imipenem Pathogen Minimum Inhibitory Concentrations MIC (Mμ/mL) Disk Diffusion Zone Diameter (mm) S I R S I R Enterobacteriaceae ≤ 1.0 2.0 ≥ 4.0 ≥ 23 20-22 ≤ 19 Pseudomonas aeruginosa ≤ 2 4 ≥ 8 ≥ 19 16-18 ≤ 15 Acinetobacter spp. ≤ 4 8 ≥ 16 ≥ 16 14-15 ≤ 13 Staphylococcus spp.* ≤ 4 8 ≥ 16 ≥ 16 14-15 ≤ 13 Haemophilus influenzae and H. parainfluenzae† ≤ 4 - - ≥ 16 - - Streptococcus pneumoniae‡ ≤ 0.12 0.25-0.5 ≥ 1 - - - Anaerobes ≤ 4.0 8.0 ≥ 16.0 - - - * For oxacillin-susceptible S. aureus and coagulase negative staphylococci results for carbapenems, including imipenem, if tested, should be reported according to the results generated using routine interpretive criteria. For oxacillin-resistant S. aureus and coagulase negative staphylococci, other beta lactam agents, including carbapenems, may appear active in vitro but are not effective clinically. Results for beta lactam agents other than cephalosporins with anti-MRSA activity should be reported as resistant or should not be reported. † For some organism/antimicrobial combinations, the absence or rare occurrence of resistant strains precludes defining any results categories other than “susceptible”. For strains yielding results suggestive of a “non-susceptible” category, organism identification and antimicrobial susceptibility test results should be confirmed. ‡ For non-meningitis S. pneumoniae isolates, penicillin MICs ≤ 0.06 μg/mL (or oxacillin zones ≥ 20 mm) indicate susceptibility to imipenem. A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound at the infection site reaches the concentrations usually achievable. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound at the infection site reaches the concentrations usually achievable, and that other therapy should be selected. Quality Control Standardized susceptibility test procedures require the use of laboratory control microorganisms to ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test. Quality control microorganisms are specific strains of organisms with intrinsic biological properties. QC strains are very stable strains which will give a standard and repeatable susceptibility pattern. The specific strains used for microbiological quality control are not clinically significant. Standard imipenem powder should provide the following range of values noted in Table 2.2 Table 2: Acceptable Quality Control Ranges for Imipenem Microorganism Minimum Inhibitory Concentrations MIC Range (μg/mL) Disk Diffusion Zone Diameter (mm) Pseudomonas aeruginosa ATCC 27853 1-4 20-28 Escherichia coli ATCC 25922 0.06-0.25 26-32 Haemophilus influenzae ATCC 49247 - 21-29 Haemophilus influenzae ATCC 49766 0.25-1.0 - Staphylococcus aureus ATCC 29213 0.015-0.06 - Enterococcus faecalis ATCC 29212 0.5-2.0 - Streptococcus pneumoniae ATCC 49619 0.03-0.12 - Bacteroides fragilis ATCC 25285 0.03-0.25* 0.03-0.125† - Bacteroides thetaiotaomicron ATCC 29741 0.25-1.0* 0.125-0.5† - Eubacterium lentum ATCC 43055 0.25-2.0* 0.125-0.5† - * Quality control ranges for broth microdilution testing † Quality control ranges for agar dilution testing REFERENCES 1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard -9th ed. CLSI document M07-A9. CLSI, 950 West Valley Rd., Suite 2500, Wayne, PA 19087, 2012. 2. CLSI. Performance Standards for Antimicrobial Susceptibility Testing; 22nd Informational Supplement. CLSI document M100S22, 2012. 3. CLSI. Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard – 11th ed. CLSI document M02-A11, 2012. 4.CLSI. Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard – 8th ed. CLSI document M11-A8, 2012.

PRIMAXIN® I.V. (imipenem and cilastatin) for Injection To reduce the development of drug-resistant bacteria and maintain the effectiveness of PRIMAXIN® I.V. and other antibacterial drugs, PRIMAXIN I.V. should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. For Intravenous Injection Only DESCRIPTION PRIMAXIN I.V. (Imipenem and Cilastatin for Injection) is a sterile formulation of imipenem (a thienamycin antibiotic) and cilastatin sodium (the inhibitor of the renal dipeptidase, dehydropeptidase l), with sodium bicarbonate added as a buffer. PRIMAXIN I.V. is a potent broad spectrum antibacterial agent for intravenous administration. Imipenem (N-formimidoylthienamycin monohydrate) is a crystalline derivative of thienamycin, which is produced by Streptomyces cattleya. Its chemical name is (5R,6S)-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 C12H17N3O4S•H2O, 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 C16H25N2O5SNa, and its structural formula is: PRIMAXIN I.V. 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 Compatibility And Stability.) PRIMAXIN I.V. 250 contains 18.8 mg of sodium (0.8 mEq) and PRIMAXIN I.V. 500 contains 37.5 mg of sodium (1.6 mEq). Solutions of PRIMAXIN I.V. range from colorless to yellow. Variations of color within this range do not affect the potency of the product.

INDICATIONS PRIMAXIN I.V. is indicated for the treatment of serious infections caused by susceptible strains of the designated microorganisms in the conditions listed below: Lower respiratory tract infections. Staphylococcus aureus (penicillinase-producing strains), Acinetobacter species, Enterobacter species, Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae1, Klebsiella species, Serratia marcescens Urinary tract infections (complicated and uncomplicated). Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains)1, Enterobacter species, Escherichia coli, Klebsiella species, Morganella morganii1, Proteus vulgaris1, Providencia rettgeri1, Pseudomonas aeruginosa Intra-abdominal infections. Enterococcus faecalis, Staphylococcus aureus (penicillinaseproducing strains)1, Staphylococcus epidermidis, Citrobacter species, Enterobacter species, Escherichia coli, Klebsiella species, Morganella morganii1, Proteus species, Pseudomonas aeruginosa, Bifidobacterium species, Clostridium species, Eubacterium species, Peptococcus species, Peptostreptococcus species, Propionibacterium species1, Bacteroides species including B. fragilis, Fusobacterium species Gynecologic infections. Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains)1, Staphylococcus epidermidis, Streptococcus agalactiae (Group B streptococci), Enterobacter species1, Escherichia coli, Gardnerella vaginalis, Klebsiella species1, Proteus species, Bifidobacterium species1, Peptococcus species1, Peptostreptococcus species, Propionibacterium species1, Bacteroides species including B. fragilis1 Bacterial septicemia. Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Enterobacter species, Escherichia coli, Klebsiella species, Pseudomonas aeruginosa, Serratia species1, Bacteroides species including B. fragilis1 Bone and joint infections. Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Staphylococcus epidermidis, Enterobacter species, Pseudomonas aeruginosa Skin and skin structure infections. Enterococcus faecalis, Staphylococcus aureus (penicillinaseproducing strains), Staphylococcus epidermidis, Acinetobacter species, Citrobacter species, Enterobacter species, Escherichia coli, Klebsiella species, Morganella morganii, Proteus vulgaris, Providencia rettgeri1, Pseudomonas aeruginosa, Serratia species, Peptococcus species, Peptostreptococcus species, Bacteroides species including B. fragilis, Fusobacterium species1 Endocarditis. Staphylococcus aureus (penicillinase-producing strains) Polymicrobic infections. PRIMAXIN I.V. is indicated for polymicrobic infections including those in which S. pneumoniae (pneumonia, septicemia), S. pyogenes (skin and skin structure), or nonpenicillinaseproducing S. aureus is one of the causative organisms. However, monobacterial infections due to these organisms are usually treated with narrower spectrum antibiotics, such as penicillin G. PRIMAXIN I.V. is not indicated in patients with meningitis because safety and efficacy have not been established. For Pediatric Use information, see PRECAUTIONS, Pediatric Use, and DOSAGE AND ADMINISTRATION sections. Because of its broad spectrum of bactericidal activity against gram-positive and gram-negative aerobic and anaerobic bacteria, PRIMAXIN I.V. is useful for the treatment of mixed infections and as presumptive therapy prior to the identification of the causative organisms. Although clinical improvement has been observed in patients with cystic fibrosis, chronic pulmonary disease, and lower respiratory tract infections caused by Pseudomonas aeruginosa, bacterial eradication may not necessarily be achieved. As with other beta-lactam antibiotics, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with PRIMAXIN I.V. During therapy of Pseudomonas aeruginosa infections, periodic susceptibility testing should be done when clinically appropriate. Infections resistant to other antibiotics, for example, cephalosporins, penicillin, and aminoglycosides, have been shown to respond to treatment with PRIMAXIN I.V. To reduce the development of drug-resistant bacteria and maintain the effectiveness of PRIMAXIN I.V. and other antibacterial drugs, PRIMAXIN I.V. 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. REFERENCE 1Efficacy for this organism in this organ system was studied in fewer than 10 infections. DOSAGE AND ADMINISTRATION Adults The dosage recommendations for PRIMAXIN I.V. represent the quantity of imipenem to be administered. An equivalent amount of cilastatin is also present in the solution. Each 125 mg, 250 mg, or 500 mg dose should be given by intravenous administration over 20 to 30 minutes. Each 750 mg or 1000 mg dose should be infused over 40 to 60 minutes. In patients who develop nausea during the infusion, the rate of infusion may be slowed. The total daily dosage for PRIMAXIN I.V. should be based on the type or severity of infection and given in equally divided doses based on consideration of degree of susceptibility of the pathogen(s), renal function, and body weight. Adult patients with impaired renal function, as judged by creatinine clearance ≤ 70 mL/min/1.73 m², require adjustment of dosage as described in the succeeding section of these guidelines. Intravenous Dosage Schedule for Adults with Normal Renal Function and Body Weight ≥ 70 kg Doses cited in Table 3 are based on a patient with normal renal function and a body weight of 70 kg. These doses should be used for a patient with a creatinine clearance of ≥ 71 mL/min/1.73 m² and a body weight of ≥ 70 kg. A reduction in dose must be made for a patient with a creatinine clearance of ≤ 70 mL/min/1.73 m² and/or a body weight less than 70 kg. (See Tables 4 and 5.) Dosage regimens in column A of Table 3 are recommended for infections caused by fully susceptible organisms which represent the majority of pathogenic species. Dosage regimens in column B of Table 3 are recommended for infections caused by organisms with moderate susceptibility to imipenem, primarily some strains of P. aeruginosa. TABLE 3: INTRAVENOUS DOSAGE SCHEDULE FOR ADULTS WITH NORMAL RENAL FUNCTION AND BODY WEIGHT ≥ 70 kg Type or Severity of Infection A Fully susceptible organisms including gram-positive and gram-negative aerobes and anaerobes B Moderately susceptible organisms, primarily some strains of P. aeruginosa Mild 250 mg q6h (TOTAL DAILY DOSE = 1.0g) 500 mg q6hm (TOTAL DAILY DOSE = 2.0g) Moderate 500 mg q8h (TOTAL DAILY DOSE = 1.5g) or 500 mg q6h (TOTAL DAILY DOSE = 2.0g) 500 mg q6h (TOTAL DAILY DOSE = 2.0g) or 1 g q8h (TOTAL DAILY DOSE = 3.0g) Severe, life threatening only 500 mg q6h (TOTAL DAILY DOSE = 2.0g) 1 g q8h (TOTAL DAILY DOSE = 3.0g) or 1 g q6h (TOTAL DAILY DOSE = 4.0g) Uncomplicated urinary tract infection 250 mg q6h (TOTAL DAILY DOSE = 1.0g) 250 mg q6h (TOTAL DAILY DOSE = 1.0g) Complicated urinary tract infection 500 mg q6h (TOTAL DAILY DOSE = 2.0g) 500 mg q6h (TOTAL DAILY DOSE = 2.0g) Due to the high antimicrobial activity of PRIMAXIN I.V., it is recommended that the maximum total daily dosage not exceed 50 mg/kg/day or 4.0 g/day, whichever is lower. There is no evidence that higher doses provide greater efficacy. However, patients over twelve years of age with cystic fibrosis and normal renal function have been treated with PRIMAXIN I.V. at doses up to 90 mg/kg/day in divided doses, not exceeding 4.0 g/day. Reduced Intravenous Schedule for Adults with Impaired Renal Function and/or Body Weight < 70 kg Patients with creatinine clearance of ≤ 70 mL/min/1.73 m² and/or body weight less than 70 kg require dosage reduction of PRIMAXIN I.V. as indicated in the tables below. Creatinine clearance may be calculated from serum creatinine concentration by the following equation: Tcc (Males) = (wt. in kg) (140 – age) /(72) (creatinine in mg/dL) Tcc (Females) = 0.85 × above value To determine the dose for adults with impaired renal function and/or reduced body weight: Choose a total daily dose from Table 3 based on infection characteristics. If the total daily dose is 1.0 g, 1.5 g, or 2.0 g, use the appropriate subsection of Table 4 and continue with step 3. If the total daily dose is 3.0 g or 4.0 g, use the appropriate subsection of Table 5 and continue with step 3. From Table 4 or 5: Select the body weight on the far left which is closest to the patient's body weight (kg). Select the patient's creatinine clearance category. Where the row and column intersect is the reduced dosage regimen. TABLE 4: REDUCED INTRAVENOUS DOSAGE OF PRIMAXIN I.V. IN ADULT PATIENTS WITH IMPAIRED RENAL FUNCTION AND/OR BODY WEIGHT < 70 kg And Body Weight (kg)is: If TOTAL DAILY DOSE from TABLE 3 is: 1.0 g/day 1.5 g/day 2.0 g/day and creatinine clearance (mL/min/1.73 m²) is: and creatinine clearance (mL/min/1.73 m²) is: and creatinine clearance (mL/min/1.73 m²) is: ≥ 71 41-70 21-40 6-20 ≥ 71 41-70 21-40 6-20 ≥ 71 41-70 21-40 6-20 then the reduced dosage regimen(mg) is: then the reduced dosage regimen(mg) is: then the reduced dosage regimen(mg) is: ≥ 70 250q6h 250q8h 250q12h 250q12h 500q8h 250q6h 250q8h 250q12h 500q6h 500q8h 250q6h 250q12h 60 250q8h 125q6h 250q12h 125q12h 250q6h 250q8h 250q8h 250q12h 500q8h 250q6h 250q8h 250q12h 50 125q6h 125q6h 125q8h 125q12h 250q6h 250q8h 250q12h 250q12h 250q6h 250q6h 250q8h 250q12h 40 125q6h 125q8h 125q12h 125q12h 250q8h 125q6h 125q8h 125q12h 250q6h 250q8h 250q12h 250q12h 30 125q8h 125q8h 125q12h 125q12h 125q6h 125q8h 125q8h 125q12h 250q8h 125q6h 125q8h 125q12h TABLE 5: REDUCED INTRAVENOUS DOSAGE OF PRIMAXIN I.V. IN ADULT PATIENTS WITH IMPAIRED RENAL FUNCTION AND/OR BODY WEIGHT < 70 kg And Body Weight(kg )Is: If TOTAL DAILY DOSE from TABLE 3 is: 3.0 g/day 4.0 g/day and creatinine clearance (mL/min/1.73 m²) is: and creatinine clearance (mL/min/1.73 m²) is: ≥ 71 41-70 21-40 6-20 ≥ 71 41-70 21-40 6-20 then the reduced dosage regimen (mg) is: then the reduced dosage regimen (mg) is: ≥ 70 1000q8h 500q6h 500q8h 500q12h 1000q6h 750q8h 500q6h 500q12h 60 750q8h 500q8h 500q8h 500q12h 1000q8h 750q8h 500q8h 500q12h 50 500q6h 500q8h 250q6h 250q12h 750q8h 500q6h 500q8h 500q12h 40 500q8h 250q6h 250q8h 250q12h 500q6h 500q8h 250q6h 250q12h 30 250q6h 250q8h 250q8h 250q12h 500q8h 250q6h 250q8h 250q12h Patients with creatinine clearances of 6 to 20 mL/min/1.73 m² should be treated with PRIMAXIN I.V. 125 mg or 250 mg every 12 hours for most pathogens. There may be an increased risk of seizures when doses of 500 mg every 12 hours are administered to these patients. Patients with creatinine clearance ≤ 5 mL/min/1.73 m² should not receive PRIMAXIN I.V. unless hemodialysis is instituted within 48 hours. There is inadequate information to recommend usage of PRIMAXIN I.V. for patients undergoing peritoneal dialysis. Hemodialysis When treating patients with creatinine clearances of ≤ 5 mL/min/1.73 m² who are undergoing hemodialysis, use the dosage recommendations for patients with creatinine clearances of 6-20 mL/min/1.73 m². (See Reduced Intravenous Dosage Schedule for Adults with Impaired Renal Function and/or Body Weight < 70 kg.) Both imipenem and cilastatin are cleared from the circulation during hemodialysis. The patient should receive PRIMAXIN I.V. after hemodialysis and at 12 hour intervals timed from the end of that hemodialysis session. Dialysis patients, especially those with background CNS disease, should be carefully monitored; for patients on hemodialysis, PRIMAXIN I.V. is recommended only when the benefit outweighs the potential risk of seizures. (See PRECAUTIONS.) Pediatric Patients See PRECAUTIONS, Pediatric Patients. For pediatric patients ≥ 3 months of age, the recommended dose for non-CNS infections is 15-25 mg/kg/dose administered every six hours. Based on studies in adults, the maximum daily dose for treatment of infections with fully susceptible organisms is 2.0 g per day, and of infections with moderately susceptible organisms (primarily some strains of P. aeruginosa) is 4.0 g/day. Higher doses (up to 90 mg/kg/day in older children) have been used in patients with cystic fibrosis. For pediatric patients ≤ 3 months of age (weighing ≥ 1,500 g), the following dosage schedule is recommended for non-CNS infections: < 1 wk of age: 25 mg/kg every 12 hrs 1-4 wks of age: 25 mg/kg every 8 hrs 4 wks-3 mos. of age: 25 mg/kg every 6 hrs. Doses less than or equal to 500 mg should be given by intravenous infusion over 15 to 30 minutes. Doses greater than 500 mg should be given by intravenous infusion over 40 to 60 minutes. PRIMAXIN I.V. is not recommended in pediatric patients with CNS infections because of the risk of seizures. PRIMAXIN I.V. is not recommended in pediatric patients < 30 kg with impaired renal function, as no data are available. Preparation Of Solution Vials Contents of the vials must be suspended and transferred to 100 mL of an appropriate infusion solution. A suggested procedure is to add approximately 10 mL from the appropriate infusion solution (see list of diluents under Compatibility And Stability) to the vial. Shake well and transfer the resulting suspension to the infusion solution container. Benzyl alcohol as a preservative has been associated with toxicity in neonates. While toxicity has not been demonstrated in pediatric patients greater than three months of age, small pediatric patients in this age range may also be at risk for benzyl alcohol toxicity. Therefore, diluents containing benzyl alcohol should not be used when PRIMAXIN I.V. is constituted for administration to pediatric patients in this age range. CAUTION: THE SUSPENSION IS NOT FOR DIRECT INFUSION. Repeat with an additional 10 mL of infusion solution to ensure complete transfer of vial contents to the infusion solution. The resulting mixture should be agitated until clear. ADD-Vantage®5Vials See separate INSTRUCTIONS FOR USE OF 'PRIMAXIN I.V.' IN ADD-Vantage® VIALS. PRIMAXIN I.V. in ADD-Vantage® vials should be reconstituted with ADD-Vantage® diluent containers containing 100 mL of either 0.9% Sodium Chloride Injection or 100 mL 5% Dextrose Injection. Compatibility And Stability Before Reconstitution The dry powder should be stored at a temperature below 25°C (77°F). Reconstituted Solutions Solutions of PRIMAXIN I.V. range from colorless to yellow. Variations of color within this range do not affect the potency of the product. Vials PRIMAXIN I.V., as supplied in single use vials and reconstituted with the following diluents (see Preparation Of Solution), maintains satisfactory potency for 4 hours at room temperature or for 24 hours under refrigeration (5°C). Solutions of PRIMAXIN I.V. should not be frozen. 0.9% Sodium Chloride Injection 5% or 10% Dextrose Injection 5% Dextrose and 0.9% Sodium Chloride Injection 5% Dextrose Injection with 0.225% or 0.45% saline solution 5% Dextrose Injection with 0.15% potassium chloride solution Mannitol 5% and 10% ADD-Vantage® vials PRIMAXIN I.V., as supplied in single dose ADD-Vantage® vials and reconstituted with the following diluents (see Preparation Of Solution), maintains satisfactory potency for 4 hours at room temperature. 0.9% Sodium Chloride Injection 5% Dextrose Injection PRIMAXIN I.V. should not be mixed with or physically added to other antibiotics. However, PRIMAXIN I.V. may be administered concomitantly with other antibiotics, such as aminoglycosides. HOW SUPPLIED PRIMAXIN I.V. is supplied as a sterile powder mixture in single dose containers including vials and ADD-Vantage® vials containing imipenem (anhydrous equivalent) and cilastatin sodium as follows: No. 3514 — 250 mg imipenem equivalent and 250 mg cilastatin equivalent and 10 mg sodium bicarbonate as a buffer No. 3516 — 500 mg imipenem equivalent and 500 mg cilastatin equivalent and 20 mg sodium bicarbonate as a buffer NDC 0006-3516-59 in trays of 25 vials. No. 3551 — 250 mg imipenem equivalent and 250 mg cilastatin equivalent and 10 mg sodium bicarbonate as a buffer NDC 0006-3551-58 in trays of 25 ADD-Vantage® vials. No. 3552 — 500 mg imipenem equivalent and 500 mg cilastatin equivalent and 20 mg sodium bicarbonate as a buffer NDC 0006-3552-59 in trays of 25 ADD-Vantage® vials. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ 08889, USA. Revised: December 2014.

PATIENT INFORMATION Patients should be counseled to inform their physician if they are taking valproic acid or divalproex sodium. Valproic acid concentrations in the blood may drop below the therapeutic range upon coadministration with PRIMAXIN I.V. If treatment with PRIMAXIN I.V. is necessary and continued, alternative or supplemental anti-convulsant medication to prevent and/or treat seizures may be needed. Patients should be counseled that antibacterial drugs including PRIMAXIN I.V. should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When PRIMAXIN I.V. is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by PRIMAXIN I.V. or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibiotics, which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

OVERDOSE The acute intravenous toxicity of imipenem-cilastatin sodium in a ratio of 1:1 was studied in mice at doses of 751 to 1359 mg/kg. Following drug administration, ataxia was rapidly produced and clonic convulsions were noted in about 45 minutes. Deaths occurred within 4-56 minutes at all doses. The acute intravenous toxicity of imipenem-cilastatin sodium was produced within 5-10 minutes in rats at doses of 771 to 1583 mg/kg. In all dosage groups, females had decreased activity, bradypnea, and ptosis with clonic convulsions preceding death; in males, ptosis was seen at all dose levels while tremors and clonic convulsions were seen at all but the lowest dose (771 mg/kg). In another rat study, female rats showed ataxia, bradypnea, and decreased activity in all but the lowest dose (550 mg/kg); deaths were preceded by clonic convulsions. Male rats showed tremors at all doses and clonic convulsions and ptosis were seen at the two highest doses (1130 and 1734 mg/kg). Deaths occurred between 6 and 88 minutes with doses of 771 to 1734 mg/kg. In the case of overdosage, discontinue PRIMAXIN I.V., treat symptomatically, and institute supportive measures as required. Imipenem-cilastatin sodium is hemodialyzable. However, usefulness of this procedure in the overdosage setting is questionable. CONTRAINDICATIONS PRIMAXIN I.V. is contraindicated in patients who have shown hypersensitivity to any component of this product.

SIDE EFFECTS Adults PRIMAXIN I.V. is generally well tolerated. Many of the 1,723 patients treated in clinical trials were severely ill and had multiple background diseases and physiological impairments, making it difficult to determine causal relationship of adverse experiences to therapy with PRIMAXIN I.V. Local Adverse Reactions Adverse local clinical reactions that were reported as possibly, probably, or definitely related to therapy with PRIMAXIN I.V. were: Phlebitis/thrombophlebitis — 3.1% Pain at the injection site — 0.7% Erythema at the injection site — 0.4% Vein induration — 0.2% Infused vein infection — 0.1% Systemic Adverse Reactions The most frequently reported systemic adverse clinical reactions that were reported as possibly, probably, or definitely related to PRIMAXIN I.V. were nausea (2.0%), diarrhea (1.8%), vomiting (1.5%), rash (0.9%), fever (0.5%), hypotension (0.4%), seizures (0.4%) (see PRECAUTIONS), dizziness (0.3%), pruritus (0.3%), urticaria (0.2%), somnolence (0.2%). Additional adverse systemic clinical reactions reported as possibly, probably, or definitely drug related occurring 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: Gastrointestinal — pseudomembranous colitis (the onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment, see WARNINGS), hemorrhagic colitis, hepatitis (including fulminant hepatitis), hepatic failure, jaundice, gastroenteritis, abdominal pain, glossitis, tongue papillar hypertrophy, staining of the teeth and/or tongue, heartburn, pharyngeal pain, increased salivation; Hematologic — pancytopenia, bone marrow depression, thrombocytopenia, neutropenia, leukopenia, hemolytic anemia; CNS — encephalopathy, tremor, confusion, myoclonus, paresthesia, vertigo, headache, psychic disturbances including hallucinations, dyskinesia, agitation; Special Senses — hearing loss, tinnitus, taste perversion; Respiratory — chest discomfort, dyspnea, hyperventilation, thoracic spine pain; Cardiovascular — palpitations, tachycardia; Skin — Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, angioneurotic edema, flushing, cyanosis, hyperhidrosis, skin texture changes, candidiasis, pruritus vulvae; Body as a whole — polyarthralgia, asthenia/weakness, drug fever; Renal — acute renal failure, oliguria/anuria, polyuria, urine discoloration. The role of PRIMAXIN I.V. in changes in renal function is difficult to assess, since factors predisposing to pre-renal azotemia or to impaired renal function usually have been present. Adverse Laboratory Changes Adverse laboratory changes without regard to drug relationship that were reported during clinical trials or reported since the drug was marketed were: Hepatic: Increased ALT (SGPT), AST (SGOT), alkaline phosphatase, bilirubin, and LDH Hemic: Increased eosinophils, positive Coombs test, increased WBC, increased platelets, decreased hemoglobin and hematocrit, agranulocytosis, 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 In studies of 178 pediatric patients ≥ 3 months of age, the following adverse events were noted: The Most Common Clinical Adverse Experiences Without Regard to Drug Relationship (Patient Incidence > 1%) Adverse Experience No. of Patients (%) Digestive System Diarrhea 7* (3.9) Gastroenteritis 2 (1.1) Vomiting 2* (1.1) Skin Rash 4 (2.2) Irritation, I.V. site 2 (1.1) Urogenital System Urine discoloration 2 (1.1) Cardiovascular System Phlebitis 4 (2.2) *One patient had both vomiting and diarrhea and is counted in each category. In studies of 135 patients (newborn to 3 months of age), the following adverse events were noted: The Most Common Clinical Adverse Experiences Without Regard to Drug Relationship (Patient Incidence > 1%) Adverse Experience No. of Patients (%) Digestive System Diarrhea 4 (3.0%) Oral Candidiasis 2 (1.5%) Skin Rash 2 (1.5%) Urogenital System Oliguria/anuria 3 (2.2%) Cardiovascular System Tachycardia 2 (1.5%) Nervous System Convulsions 8 (5.9%) Patients ( ≥ 3 Months of Age) With Normal Pretherapy but Abnormal During Therapy Laboratory Values Laboratory Parameter Abnormality No. of Patients With Abnormalities/ No. of Patients With Lab Done (%) Hemoglobin Age < 5 mos.: < 10 gm % 6 mos.-12 yrs.: < 11.5 gm % 19/129 (14.7) Hematocrit Age < 5 mos.: < 30 vol % 6 mos.-12 yrs.: < 34.5 vol % 23/129 (17.8) Neutrophils ≤ 1000/mm³ (absolute) 4/123 (3.3) Eosinophils ≥ 7% 15/117 (12.8) Platelet Count ≥ 500 ths/mm³ 16/119 (13.4) Urine Protein ≥ 1 8/97 (8.2) Serum Creatinine > 1.2 mg/dL 0/105 (0) BUN > 22 mg/dL 0/108 (0) AST (SGOT) > 36 IU/L 14/78 (17.9) ALT (SGPT) > 30 IU/L 10/93 (10.8) Patients ( < 3 Months of Age) With Normal Pretherapy but Abnormal During Therapy Laboratory Values Laboratory Parameter No. of Patients With Abnormalities* (%) Eosinophil Count↑ 11 (9.0%) Hematocrit↓ 3 (2.0%) Hematocrit↑ 1 (1.0%) Platelet Count↑ 5 (4.0%) Platelet Count↓ 2 (2.0%) Serum Creatinine↑ 5 (5.0%) Bilirubin↑ 3 (3.0%) Bilirubin↓ 1 (1.0%) AST (SGOT)↑ 5 (6.0%) ALT (SGPT)↑ 3 (3.0%) Serum Alkaline Phosphate↑ 2 (3.0%) *The denominator used for percentages was the number of patients for whom the test was performed during or posttreatment and, therefore, varies by test. Examination of published literature and spontaneous adverse event reports suggested a similar spectrum of adverse events in adult and pediatric patients. DRUG INTERACTIONS Generalized seizures have been reported in patients who received ganciclovir and PRIMAXIN. These drugs should not be used concomitantly unless the potential benefits outweigh the risks. Since concomitant administration of PRIMAXIN and probenecid results in only minimal increases in plasma levels of imipenem and plasma half-life, it is not recommended that probenecid be given with PRIMAXIN. PRIMAXIN should not be mixed with or physically added to other antibiotics. However, PRIMAXIN may be administered concomitantly with other antibiotics, such as aminoglycosides. Case reports in the literature have shown that co-administration of carbapenems, including imipenem, 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, Seizure Potential).

WARNINGS SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC) REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING THERAPY W ITH BETA-LACTAMS. THESE REACTIONS ARE MORE APT TO OCCUR IN PERSONS W ITH A HISTORY OF SENSITIVITY TO MULTIPLE ALLERGENS. THERE HAVE BEEN REPORTS OF PATIENTS W ITH A HISTORY OF PENICILLIN HYPERSENSITIVITY W HO HAVE EXPERIENCED SEVERE HYPERSENSITIVITY REACTIONS W HEN TREATED W ITH ANOTHER BETA-LACTAM. BEFORE INITIATING THERAPY W ITH PRIMAXIN I.V., CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OTHER BETA-LACTAMS, AND OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, PRIMAXIN SHOULD BE DISCONTINUED. SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS, AND AIRWAY MANAGEMENT, INCLUDING INTUBATION, MAY ALSO BE ADMINISTERED AS INDICATED. Seizure Potential Seizures and other CNS adverse experiences, such as confusional states and myoclonic activity, have been reported during treatment with PRIMAXIN I.V. (See PRECAUTIONS and ADVERSE REACTIONS.) Case reports in the literature have shown that co-administration of carbapenems, including imipenem, 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 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 PRIMAXIN I.V. is necessary, supplemental anticonvulsant therapy should be considered (see PRECAUTIONS: DRUG INTERACTIONS). Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including PRIMAXIN I.V., 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 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 C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. PRECAUTIONS General CNS adverse experiences such as confusional states, myoclonic activity, and seizures have been reported during treatment with PRIMAXIN I.V., especially when recommended dosages were exceeded. These experiences have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) and/or compromised renal function. However, there have been reports of CNS adverse experiences in patients who had no recognized or documented underlying CNS disorder or compromised renal function. When recommended doses were exceeded, adult patients with creatinine clearances of ≤ 20 mL/min/1.73 m², whether or not undergoing hemodialysis, had a higher risk of seizure activity than those without impairment of renal function. Therefore, close adherence to the dosing guidelines for these patients is recommended. (See DOSAGE AND ADMINISTRATION.) Patients with creatinine clearances of ≤ 5 mL/min/1.73 m² should not receive PRIMAXIN I.V. unless hemodialysis is instituted within 48 hours. For patients on hemodialysis, PRIMAXIN I.V. is recommended only when the benefit outweighs the potential risk of seizures. Close adherence to the recommended dosage and dosage schedules 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 PRIMAXIN I.V. re-examined to determine whether it should be decreased or the antibiotic discontinued. As with other antibiotics, prolonged use of PRIMAXIN I.V. 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 PRIMAXIN I.V. 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 PRIMAXIN I.V. possesses the characteristic low toxicity of the beta-lactam group of antibiotics, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy. Carcinogenesis, Mutagenesis, Impairment Of Fertility Long term studies in animals have not been performed to evaluate carcinogenic potential of imipenemcilastatin. Genetic toxicity studies were performed in a variety of bacterial and mammalian tests in vivo and in vitro. The tests used were: V79 mammalian cell mutagenesis assay (imipenem-cilastatin sodium alone and imipenem alone), Ames test (cilastatin sodium alone and imipenem alone), unscheduled DNA synthesis assay (imipenem-cilastatin sodium) and in vivo mouse cytogenetics test (imipenem-cilastatin sodium). None of these tests showed any evidence of genetic alterations. Reproductive tests in male and female rats were performed with imipenem-cilastatin sodium at intravenous doses up to 80 mg/kg/day and at a subcutaneous dose of 320 mg/kg/day, approximately equal to the highest recommended human dose of the intravenous formulation (on a mg/m² body surface area basis). Slight decreases in live fetal body weight were restricted to the highest dosage level. No other adverse effects were observed on fertility, reproductive performance, fetal viability, growth or postnatal development of pups. Pregnancy Teratogenic Effects Pregnancy Category C Teratology studies with cilastatin sodium at doses of 30, 100, and 300 mg/kg/day administered intravenously to rabbits and 40, 200, and 1000 mg/kg/day administered subcutaneously to rats, up to approximately 1.9 and 3.2 times 2 the maximum recommended daily human dose (on a mg/m² body surface area basis) of the intravenous formulation of imipenem-cilastatin sodium (50 mg/kg/day) in the two species, respectively, showed no evidence of adverse effect on the fetus. No evidence of teratogenicity was observed in rabbits given imipenem at intravenous doses of 15, 30 or 60 mg/kg/day and rats given imipenem at intravenous doses of 225, 450, or 900 mg/kg/day, up to approximately 0.4 and 2.9 times2 the maximum recommended daily human dose (on a mg/m² body surface area basis) in the two species, respectively. Teratology studies with imipenem-cilastatin sodium at intravenous doses of 20 and 80, and a subcutaneous dose of 320 mg/kg/day, up to 0.5 times2 (mice) to approximately equal to (rats) the highest recommended daily intravenous human dose (on a mg/m² body surface area basis) in pregnant rodents during the period of major organogenesis, revealed no evidence of teratogenicity. Imipenem-cilastatin sodium, when administered subcutaneously to pregnant rabbits at dosages equivalent to the usual human dose of the intravenous formulation and higher (1000-4000 mg/day), caused body weight loss, diarrhea, and maternal deaths. W hen comparable doses of imipenem-cilastatin sodium were given to non-pregnant rabbits, body weight loss, diarrhea, and deaths were also observed. This intolerance is not unlike that seen with other beta-lactam antibiotics in this species and is probably due to alteration of gut flora. A teratology study in pregnant cynomolgus monkeys given imipenem-cilastatin sodium at doses of 40 mg/kg/day (bolus intravenous injection) or 160 mg/kg/day (subcutaneous injection) resulted in maternal toxicity including emesis, inappetence, body weight loss, diarrhea, abortion, and death in some cases. In contrast, no significant toxicity was observed when non-pregnant cynomolgus monkeys were given doses of imipenem-cilastatin sodium up to 180 mg/kg/day (subcutaneous injection). W hen doses of imipenemcilastatin sodium (approximately 100 mg/kg/day or approximately 0.6 times2 the maximum recommended daily human dose of the intravenous formulation) were administered to pregnant cynomolgus monkeys at an intravenous infusion rate which mimics human clinical use, there was minimal maternal intolerance (occasional emesis), no maternal deaths, no evidence of teratogenicity, but an increase in embryonic loss relative to control groups. No adverse effects on the fetus or on lactation were observed when imipenem-cilastatin sodium was administered subcutaneously to rats late in gestation at dosages up to 320 mg/kg/day, approximately equal to the highest recommended human dose (on a mg/m² body surface area basis). There are, however, no adequate and well-controlled studies in pregnant women. PRIMAXIN I.V. should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus. Nursing Mothers It is not known whether imipenem-cilastatin sodium is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PRIMAXIN I.V. is administered to a nursing woman. Pediatric Use Use of PRIMAXIN I.V. in pediatric patients, neonates to 16 years of age, is supported by evidence from adequate and well-controlled studies of PRIMAXIN I.V. in adults and by the following clinical studies and published literature in pediatric patients: Based on published studies of 1783 pediatric patients ≥ 3 months of age (with non-CNS infections), the recommended dose of PRIMAXIN I.V. is 15-25 mg/kg/dose administered every six hours. Doses of 25 mg/kg/dose in patients 3 months to < 3 years of age, and 15 mg/kg/dose in patients 3-12 years of age were associated with mean trough plasma concentrations of imipenem of 1.1±0.4 μg/mL and 0.6±0.2 μg/mL following multiple 60-minute infusions, respectively; trough urinary concentrations of imipenem were in excess of 10 μg/mL for both doses. These doses have provided adequate plasma and urine concentrations for the treatment of non-CNS infections. Based on studies in adults, the maximum daily dose for treatment of infections with fully susceptible organisms is 2.0 g per day, and of infections with moderately susceptible organisms (primarily some strains of P. aeruginosa) is 4.0 g/day. (See DOSAGE AND ADMINISTRATION, Table 3.) Higher doses (up to 90 mg/kg/day in older children) have been used in patients with cystic fibrosis. (See DOSAGE AND ADMINISTRATION.) Based on studies of 1354 pediatric patients ≤ 3 months of age (weighing ≥ 1,500 g), the following dosage schedule is recommended for non-CNS infections: < 1 wk of age: 25 mg/kg every 12 hrs 1-4 wks of age: 25 mg/kg every 8 hrs 4 wks-3 mos. of age: 25 mg/kg every 6 hrs. In a published dose-ranging study of smaller premature infants (670-1,890 g) in the first week of life, a dose of 20 mg/kg q12h by 15-30 minutes infusion was associated with mean peak and trough plasma imipenem concentrations of 43 μg/mL and 1.7 μg/mL after multiple doses, respectively. However, moderate accumulation of cilastatin in neonates may occur following multiple doses of PRIMAXIN I.V. The safety of this accumulation is unknown. PRIMAXIN I.V. is not recommended in pediatric patients with CNS infections because of the risk of seizures. PRIMAXIN I.V. is not recommended in pediatric patients < 30 kg with impaired renal function, as no data are available. Geriatric Use Of the approximately 3600 subjects ≥ 18 years of age in clinical studies of PRIMAXIN I.V., including postmarketing studies, approximately 2800 received PRIMAXIN I.V. Of the subjects who received PRIMAXIN I.V., 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, Adults). Dosage adjustment in the case of renal impairment is necessary (see DOSAGE AND ADMINISTRATION, Reduced Intravenous Schedule for Adults with Impaired Renal Function and/or Body Weight < 70 kg). REFERENCES 2 Based on patient body surface area of 1.6 m² (weight of 60 kg). 3Two patients were less than 3 months of age. 4One patient was greater than 3 months of age.