CILANEM

Imipenem and Cilastatin for

Injection, USP (I.V). (imipenem and cilastatin) for Injection is a sterile formulation of imipenem, a penem antibacterial, and cilastatin, a renal dehydropeptidase inhibitor with sodium bicarbonate added as a buffer.

Injection, USP (I.V). 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.

C 16 H 25 N 2 O 5 SNa, and its structural formula is: Imipenem and Cilastatin for Injection, USP (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.

Each Imipenem and Cilastatin for

Injection, USP (I.V). 250 mg/250 mg vial contains imipenem USP 250 mg (anhydrous equivalent) and cilastatin sodium USP equivalent to 250 mg cilastatin and each 500 mg/500 mg vial contains imipenem USP 500 mg (anhydrous equivalent) and cilastatin sodium USP equivalent to 500 mg cilastatin.

In addition, the 250 mg/250 mg vial contains 10 mg of sodium bicarbonate and the 500 mg/500 mg vial contains 20 mg of sodium bicarbonate.

The sodium content of the 250 mg/250 mg vial is 18.8 mg (0.8 mEq) and the sodium content for the 500 mg/500 mg vial is 37.5 mg (1.6 mEq).

Solutions of Imipenem and Cilastatin for

Injection, USP (I.V). range from colorless to yellow.

Variations of color within this range do not affect the potency of the product.

It is used as part of the treatment of inhaled anthrax (Inhaled anthrax), and is not used for central neurological infections.

• It is used for the treatment of multi-system-resistant lungs such as the Golden Cluster Spectacular, Pseudomonas aerogenosa and Acintopacter.

The dose should be reduced in patients with kidney failure or central neurological disorders such as seizures.

Use in pregnancy

Embenem should not be used in life-threatening infections when the mother's benefit exceeds the risk to the baby.

Breastfeeding: be used with caution.

Mechanism of Action Imipenem and Cilastatin for Injection (I.V). is a combination of imipenem and cilastatin.

Imipenem is a penem antibacterial drug.

Cilastatin is a renal dehydropeptidase inhibitor that limits the renal metabolism of imipenem. 12.3 Pharmacokinetics Intravenous infusion of Imipenem and Cilastatin for Injection (I.V). over 20 minutes results in peak plasma levels of imipenem antimicrobial activity that range from to 58 mcg/mL for the 500 mg dose, and from to 83 mcg/mL for the 1,000 mg dose.

At these doses, plasma levels of imipenem antimicrobial activity decline to below 1 mcg/mL or less in to 6 hours.

Peak plasma levels of cilastatin following a 20-minute intravenous infusion of Imipenem and Cilastatin for Injection (I.V). range from to 49 mcg/mL for the 500 mg dose, and from to 88 mcg/mL for the 1,000 mg dose.

The binding of imipenem to human serum proteins is approximately 20% and that of cilastatin is approximately 40%.

Imipenem has been shown to penetrate into human tissues, including vitreous humor, aqueous humor, lung, peritoneal fluid, CSF, bone, interstitial fluid, skin, and fascia.

As there are no adequate and well-controlled studies of imipenem treatment in these additional body sites, the clinical significance of these tissue concentration data is unknown.

After a 1 gram dose of Imipenem and Cilastatin for Injection (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 in Table 9: Table 9: Average Levels of Imipenem Tissue or Fluid N Imipenem Level mcg/mL or mcg/g Range Vitreous Humor 3 3.4 (3.5 hours post dose) 2.88 to 3.6 Aqueous Humor 5 2.99 (2 hours post dose) 2.4 to 3.9 Lung Tissue 8 5.6 (median) 3.5 to 15.5 Sputum 1 2.1 — Pleural 1 22 — Peritoneal 12 23.9 S.D.±5.3 (2 hours post dose) — Bile 2 5.3 (2.25 hours post dose) 4.6 to 6 CSF (uninflamed) 5 1 (4 hours post dose) 0.26 to 2 CSF (inflamed) 7 2.6 (2 hours post dose) 0.5 to 5.5 Fallopian Tubes 1 13.6 — Endometrium 1 11.1 — Myometrium 1 5 — Bone 10 2.6 0.4 to 5.4 Interstitial Fluid 12 16.4 10 to 22.6 Skin 12 4.4 NA Fascia 12 4.4 NA Metabolism Imipenem, when administered alone, is metabolized in the kidneys by dehydropeptidase I, resulting in relatively low levels in urine.

Cilastatin, an inhibitor of this enzyme, effectively prevents renal metabolism of imipenem so that when imipenem and cilastatin sodium are given concomitantly, adequate antibacterial levels of imipenem are achieved in the urine.

The plasma half-life of each component is approximately 1 hour.

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 mcg/mL can be maintained for up to 8 hours with Imipenem and Cilastatin for Injection (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 Imipenem and Cilastatin for Injection (I.V).

Imipenem and Cilastatin for

Injection (I.V). is hemodialyzable.

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 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.

Doses of 25 mg/kg/dose in patients 3 months to < 3 years of age, and 15 mg/kg/dose in patients to 12 years of age were associated with mean trough plasma concentrations of imipenem of 1.1±0.4 mcg/mL and 0.6±0.2 mcg/mL following multiple 60-minute infusions, respectively; trough urinary concentrations of imipenem were in excess of 10 mcg/mL for both doses.

These doses have provided adequate plasma and urine concentrations for the treatment of non-CNS infections.

In a dose-ranging study of smaller premature infants (670 to 1,890 g) in the first week of life, a dose of 20 mg/kg q12h by to 30 minutes infusion was associated with mean peak and trough plasma imipenem concentrations of 43 mcg/mL and 1.7 mcg/mL after multiple doses, respectively.

However, moderate accumulation of cilastatin in neonates may occur following multiple doses of Imipenem and Cilastatin for Injection (I.V).

The safety of this accumulation is unknown. 12.4 Microbiology Mechanism of Action Imipenem and Cilastatin for Injection (I.V). is a combination of imipenem and cilastatin.

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 of Escherichia coli, and 1A, 1B, 2, 4 and of Pseudomonas aeruginosa.

The lethal effect is related to binding to PBP 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 beta-lactamases from certain Gram-negative bacteria which are inherently resistant to most beta-lactam antibacterials, e.g., Pseudomonas aeruginosa, Serratia spp., and Enterobacter spp.

Resistance Imipenem is inactive in vitro against Enterococcus faecium, Stenotrophomonas maltophilia and some isolates of Burkholderia cepacia.

Methicillin-resistant staphylococci should be reported as resistant to imipenem.

In vitro tests show imipenem to act synergistically with aminoglycoside antibacterials against some isolates of Pseudomonas aeruginosa.

Imipenem has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections.

Aerobic bacteria Gram-positive bacteria Enterococcus faecalis

Staphylococcus aureus Staphylococcus epidermidis Streptococcus agalactiae (Group B streptococci) Streptococcus pneumoniae Streptococcus pyogenes Gram-negative bacteria Acinetobacter spp.

Citrobacter spp.

Enterobacter spp.

Escherichia coli Gardnerella vaginalis Haemophilus influenzae

Haemophilus parainfluenzae Klebsiella spp.

Morganella morganii Proteus vulgaris Providencia rettgeri

Pseudomonas aeruginosa Serratia spp., including S. marcescens Anaerobic bacteria Gram positive bacteria Bifidobacterium spp.

Clostridium spp.

Eubacterium spp.

Peptococcus spp.

Peptostreptococcus spp.

Propionibacterium spp.

Gram-negative bacteria

Bacteroides spp. , including B. fragilis Fusobacterium spp.

The following in vitro data are available, but their clinical significance is unknown.

At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for imipenem against isolates of similar genus or organism group.

However, the efficacy of imipenem in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.

Aerobic bacteria Gram-positive bacteria

Bacillus spp.

Listeria monocytogenes

Nocardia spp.

Staphylococcus saprophyticus Group C streptococci Group G streptococci Viridans group streptococci Gram-negative bacteria Aeromonas hydrophila Alcaligenes spp.

Capnocytophaga spp.

Haemophilus ducreyi Neisseria gonorrhoeae

Pasteurella spp.

Providencia stuartii Anaerobic bacteria Prevotella bivia

Prevotella disiens Prevotella melaninogenica Veillonella spp.

So, his involvement with the selastin prevents deactivating the renal efficacy of ambenem, the wide spectrum anti-bacterial, positive and negative gam negative bacteria, the aerobic and anaerobic, do you have questions on this? Ask Sina, artificial intelligence to answer all your medical questions.

The following serious adverse reactions are described in greater detail in the Warnings and Precautions section.

Hypersensitivity Reactions Seizure Potential Increased Seizure Potential Due to Interaction with Valproic Acid Clostridioides difficile -Associated Diarrhea (CDAD) Development of Drug-Resistant Bacteria 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.

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.

The most frequently occurring adverse reactions (> 1%) in neonates to 3 months of age were convulsions, diarrhea, oliguria/anuria, oral candidiasis, rash, tachycardia.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.

During clinical investigations 1,723 patients were treated with Imipenem and Cilastatin for Injection (I.V).

Table 4 shows the incidence of adverse reactions reported during the clinical investigations of adult patients treated with Imipenem and Cilastatin for Injection (I.V).

Table 4: Incidence (%)* of Adverse Reactions Reported During Clinical.

Investigations of Adult Patients Treated with Imipenem and Cilastatin for Injection (I.V). * Adverse reactions with an incidence ≥ 0.2% of Imipenem and Cilastatin for Injection (I.V). -treated adult patients.

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.

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.

Table 6: Incidence (%)* 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 (I.V). Adverse reactions that occurred in > 1 % of Imipenem and Cilastatin for Injection (I.V).-treated pediatric patients (greater than or equal to 3 months of age) 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 (%) of Adverse Reactions Reported During Clinical.

Investigations of Pediatric Patients Neonates to 3 Months of Age Treated with Imipenem and Cilastatin for Injection (I.V). * Adverse reactions that occurred in > 1 % of Imipenem and Cilastatin for Injection (I.V).-treated pediatric patients (neonates to 3 months of age) 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 (I.V).

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 (I.V). 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.

In the case of overdosage, discontinue Imipenem and Cilastatin for Injection (I.V)., treat symptomatically, and institute supportive measures as required.

Imipenem and Cilastatin for

Injection (I.V). is hemodialyzable.

Imipenem and Cilastatin for

Injection (I.V). is contraindicated in patients who have shown hypersensitivity to any component of this product.

Known hypersensitivity to any component of Imipenem and Cilastatin for Injection (I.V).

The dosage of Imipenem and Cilastatin for Injection (I.V). in adult patients should be based on suspected or confirmed pathogen susceptibility.

For adult patients with normal renal function (creatinine clearance of greater than or equal to 90 mL/min), the recommended dosage regimens are: 500 mg every 6 hours OR 1,000 mg every 8 hours OR 1,000 mg every 6 hours.

See full prescribing information for dosage recommendations in pediatric patients.

A reduction in dose must be made for a patient with a creatinine clearance of less than 90 mL/min.

Patients with creatinine clearances of less than 15 mL/min should not receive Imipenem and Cilastatin for Injection (I.V). unless hemodialysis is instituted within 48 hours.

Reconstitute Imipenem and Cilastatin for

Injection, USP (I.V). vial with appropriate diluent and dilute the reconstituted suspension with an appropriate infusion solution before administering by intravenous infusion. 2.1 Dosage in Adults For Intravenous Injection Only The dosage of Imipenem and Cilastatin for Injection (I.V). in adult patients should be based on suspected or confirmed pathogen susceptibility as shown in Table 1 below.

The dosage recommendations for Imipenem and Cilastatin for Injection (I.V). represent the quantity of imipenem to be administered.

An equivalent amount of cilastatin is also present in the solution.

These doses should be used for patients with creatinine clearance of greater than or equal to 90 mL/min. A reduction in dose must be made for patients with creatinine clearance less than 90 mL/min as shown in Table 3.

Recommend that the maximum total daily dosage not exceed 4 g/day. Administer 500 mg by intravenous infusion over to 30 minutes.

Administer 1,000 mg by intravenous infusion over to 60 minutes.

In patients who develop nausea during the infusion, the rate of infusion may be slowed.

Table 1: Dosage of Imipenem and Cilastatin for Injection (I.V). in Adult Patients with Creatinine Clearance Greater than or Equal to 90 mL/min Suspected or Proven Pathogen Susceptibility Dosage of Imipenem and Cilastatin for Injection (I.V). If the infection is suspected or proven to be due to a susceptible bacterial species 500 mg every 6 hours OR 1,000 mg every 8 hours If the infection is suspected or proven to be due to bacterial species with intermediate susceptibility 1,000 mg every 6 hours 2.2 Dosage in Pediatric Patients Imipenem and Cilastatin for Injection (I.V). is not recommended in pediatric patients with CNS infections because of the risk of seizures.

Imipenem and Cilastatin for

Injection (I.V). is not recommended in pediatric patients < 30 kg with renal impairment, as no data are available.

Based on studies in adults, the maximum total daily dose in pediatric patients should not exceed 4 g/day.

The recommended dosage for pediatric patients with non-CNS infections is shown in Table 2 below: Table 2: Recommended Imipenem and Cilastatin for Injection (I.V). Dosage in Pediatric Patients for Non-CNS.

Infections Doses less than or equal to 500 mg should be given by intravenous infusion over to 30 minutes † Doses greater than 500 mg should be given by intravenous infusion over to 60 minutes Age Dose (mg/kg) , † Frequency (hours) Greater than or equal to 3 Months of Age 15-25 mg/kg Every 6 hours Less than or equal to 3 months of age (Greater than or equal to 1,500 g body weight) 4 weeks to 3 months of age 25 mg/kg Every 6 hours to 4 weeks of age 25 mg/kg Every 8 hours Less than 1 week of age 25 mg/kg Every 12 hours Recommend that the maximum total daily dosage not exceed 4 g/day 2.3 Dosage in Adult Patients with Renal Impairment Patients with creatinine clearance less than 90 mL/min require dosage reduction of Imipenem and Cilastatin for Injection (I.V). as indicated in Table 3.

The serum creatinine should represent a steady state of renal function.

Use the

Cockcroft-Gault method described below to calculate the creatinine clearance: Males: (weight in kg) x (140-age in years) x serum creatinine (mg/100 mL) Females: x (value calculated for males) Table 3: Dosage of Imipenem and Cilastatin for Injection (I.V). for Adult Patients in Various Renal Function Groups Based on Estimated Creatinine Clearance (CLcr) * Administer doses less than or equal to 500 mg by intravenous infusion over to 30 minutes.

Discard unused portion of the infusion solution. † Administer doses greater than 500 mg by intravenous infusion over to 60 minutes.

Creatinine clearance (mL/min) Greater than or equal to 90 Less than to greater than or equal to 60 Less than to greater than or equal to 30 Less than to greater than or equal to 15 Dosage of Imipenem and Cilastatin for Injection (I.V)., † If the infection is suspected or proven to be due to a susceptible bacterial species: 500 mg every 6 hours 400 mg every 6 hours 300 mg every 6 hours 200 mg every 6 hours OR 1,000 mg every 8 hours 500 mg every 6 hours 500 mg every 8 hours 500 mg every 12 hours Dosage of Imipenem and Cilastatin for Injection (I.V)., † If the infection is suspected or proven to be due to bacterial species with intermediate susceptibility: 1,000 mg every 6 hours 750 mg every 8 hours 500 mg every 6 hours 500 mg every 12 hours In patients with creatinine clearances of less than to greater than or equal to 15 mL/min, there may be an increased risk of seizures.

Patients with creatinine clearance less than 15 mL/min should not receive Imipenem and Cilastatin for Injection (I.V). unless hemodialysis is instituted within 48 hours.

There is inadequate information to recommend usage of Imipenem and Cilastatin for Injection (I.V). for patients undergoing peritoneal dialysis. 2.4 Dosage in Hemodialysis Patients When treating patients with creatinine clearances of less than 15 mL/min who are undergoing hemodialysis, use the dosage recommendations for patients with creatinine clearances of less than to greater than or equal to 15 mL/min in Table 3 above.

Both imipenem and cilastatin are cleared from the circulation during hemodialysis.

The patient should receive Imipenem and Cilastatin for Injection (I.V). after hemodialysis and at 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, Imipenem and Cilastatin for Injection (I.V). is recommended only when the benefit outweighs the potential risk of seizures. 2.5 Reconstitution and Preparation of Imipenem and Cilastatin for Injection (I.V). Solution for Intravenous Administration Imipenem and Cilastatin for Injection (I.V). Vials Do not use diluents containing benzyl alcohol to reconstitute Imipenem and Cilastatin for Injection (I.V). for administration to neonates because it 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.

Contents of the vials must be reconstituted by adding approximately 10 mL of the appropriate diluent to the vial.

List of appropriate diluents are as follows: 0.9% Sodium Chloride Injection 5% Dextrose Injection 5% Dextrose and 0.9% Sodium Chloride Injection 5% Dextrose Injection with 0.225% or 0.45% saline solution Reconstituted Solutions of Imipenem and Cilastatin for Injection (I.V). range from colorless to yellow.

Variations of color within this range do not affect the potency of the product.

The reconstituted suspension must not be administered by direct Intravenous Infusion.

After reconstitution, shake vial well and transfer the resulting suspension to 100 mL of an appropriate infusion solution before administering by intravenous infusion.

Repeat transfer of the resulting suspension with an additional 10 mL of infusion solution to ensure complete transfer of vial contents to the infusion solution.

Agitate the resulting mixture until clear.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Discard unused portion of the infusion solution where applicable. 2.6 Storage of Reconstituted Solutions Vials (After Reconstitution) Imipenem and Cilastatin for Injection (I.V)., as supplied in single dose vials and reconstituted with the appropriate diluents, maintains satisfactory potency for 4 hours at room temperature or for 24 hours under refrigeration (5°C).

Do not freeze solutions of Imipenem and Cilastatin for Injection (I.V). 2.7 Incompatibility and Compatibility of Imipenem and Cilastatin for Injection (I.V). with other Antibacterial Drugs Do not mix Imipenem and Cilastatin for Injection (I.V). with, or physically add to, other antibacterial drugs.

Injection (I.V). may be administered concomitantly with other antibacterial drugs, such as aminoglycosides.

Imipenem and Cilastatin for

Injection, USP (I.V). is supplied as a sterile powder mixture in single-dose vials containing imipenem (anhydrous equivalent) and cilastatin (free acid equivalent) as follows: Product Code Unit of Sale Strength Each PRX349025 NDC 63323-349-94 Unit of 25 250 mg imipenem equivalent and 250 mg cilastatin equivalent and 10 mg sodium bicarbonate as a buffer NDC 63323-349-41 20 mL Single-Dose Vial PRX342025 NDC 63323-322-94 Unit of 25 500 mg imipenem equivalent and 500 mg cilastatin equivalent and 20 mg sodium bicarbonate as a buffer NDC 63323-322-41 20 mL Single-Dose Vial 16.2 Storage and Handling Before Reconstitution: Imipenem and Cilastatin for Injection, USP (I.V). sterile powder should be stored at 20° to 25°C (68° to 77°F) .

Imipenem and Cilastatin for Injection, USP (I.V). sterile powder should be stored at 20° to 25°C (68° to 77°F) .

Available data from a small number of postmarketing cases with Imipenem and Cilastatin for Injection (I.V). 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.

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.

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 to 18) at doses up to 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 to 17) and intravenously to rabbits (GD to 18) at doses up to 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 to 15).

In two separate studies, imipenem/cilastatin was administered to rats (GD to 17 and GD 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.

Use of Imipenem and Cilastatin for

Injection (I.V). in pediatric patients is supported by evidence from adequate and well-controlled trials of Imipenem and Cilastatin for Injection (I.V). in adults and clinical studies in pediatric patients.

Imipenem and Cilastatin for

Injection (I.V). is not recommended in pediatric patients with CNS infections because of the risk of seizures.

Injection (I.V). is not recommended in pediatric patients less than 30 kg with renal impairment, as no data are available.

Of the approximately 3,600 subjects ≥ 18 years of age in clinical studies of Imipenem and Cilastatin for Injection (I.V)., including postmarketing studies, approximately 2,800 received Imipenem and Cilastatin for Injection (I.V).

Of the subjects who received Imipenem and Cilastatin for Injection (I.V)., data are available on approximately 800 subjects who were and over, including approximately 300 subjects who were 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.

Dosage adjustment in the case of renal impairment is necessary.