Imipenem and Cilastatin

Hospira, Inc.

IMIPENEM AND CILASTATIN FOR INJECTION, USP (I.V.)

FULL PRESCRIBING INFORMATION: CONTENTS*

• IMIPENEM AND CILASTATIN DESCRIPTION
• CLINICAL PHARMACOLOGY
• IMIPENEM AND CILASTATIN INDICATIONS AND USAGE
• IMIPENEM AND CILASTATIN CONTRAINDICATIONS
• WARNINGS
• PRECAUTIONS
• IMIPENEM AND CILASTATIN ADVERSE REACTIONS
• OVERDOSAGE
• IMIPENEM AND CILASTATIN DOSAGE AND ADMINISTRATION
• PREPARATION OF SOLUTION
• COMPATIBILITY AND STABILITY
• HOW SUPPLIED
• REFERENCES

FULL PRESCRIBING INFORMATION

Rx Only

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Imipenem and Cilastatin for Injection (I.V.) and other antibacterial drugs, Imipenem and Cilastatin for Injection (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  

IMIPENEM AND CILASTATIN DESCRIPTION

Imipenem and Cilastatin for Injection (I.V.) 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. Imipenem and Cilastatin for Injection (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 (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 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-dimethylcyclopropane carboxamido]-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:

Imipenem and Cilastatin for Injection (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 .) The 250 mg/250 mg vial contains 250 mg imipenem (anhydrous equivalent) and 250 mg cilastatin as sodium salt. The inactive ingredient is sodium bicarbonate 10 mg as a buffer. The 500 mg/500 mg vial contains 500 mg imipenem (anhydrous equivalent) and 500 mg cilastatin as sodium salt. The inactive ingredient is sodium bicarbonate 20 mg as a buffer. Imipenem and Cilastatin for Injection (I.V.) 250 mg/250 mg contains 18.8 mg of sodium (0.8 mEq) and Imipenem and Cilastatin for Injection (I.V.) 500 mg/500 mg contains 37.5 mg of sodium (1.6 mEq). 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.

After constitution it is to be solubilized in a suitable parenteral fluid prior to intravenous infusion.

CLINICAL PHARMACOLOGY

Adults
Intravenous Administration
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 14 to 24 mcg/mL for the 250 mg dose, from 21 to 58 mcg/mL for the 500 mg dose, and from 41 to 83 mcg/mL for the 1000 mg dose. At these doses, plasma levels of imipenem antimicrobial activity decline to below 1 mcg/mL or less in 4 to 6 hours. Peak plasma levels of cilastatin following a 20-minute intravenous infusion of Imipenem and Cilastatin for Injection (I.V.) range from 15 to 25 mcg/mL for the 250 mg dose, from 31 to 49 mcg/mL for the 500 mg dose, and from 56 to 88 mcg/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 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.).

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.

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 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:

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 beta-lactamases 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 mcg/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 method^1,2 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 concentrations^2,3. This procedure uses paper disks impregnated with 10-mcg 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:

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

IMIPENEM AND CILASTATIN INDICATIONS AND USAGE

Imipenem and Cilastatin for Injection (I.V.) is indicated for the treatment of serious infections caused by susceptible strains of the designated microorganisms in the conditions listed below:

(1) Lower respiratory tract infections. Staphylococcus aureus (penicillinase-producing strains), Acinetobacter species, Enterobacter species, Escherichia coli , Haemophilus influenzae , Haemophilus parainfluenzae *, Klebsiella species, Serratia marcescens

(2) Urinary tract infections (complicated and uncomplicated). Enterococcus faecalis , Staphylococcus aureus (penicillinase-producing strains)*, Enterobacter species, Escherichia coli , Klebsiella species, Morganella morganii* , Proteus vulgaris *, Providencia rettgeri * , Pseudomonas aeruginosa

(3) Intra-abdominal infections. Enterococcus faecalis , Staphylococcus aureus (penicillinase-producing strains)*, 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

(4) Gynecologic infections. Enterococcus faecalis , Staphylococcus aureus (penicillinase-producing strains)*, 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 *

(5) Bacterial septicemia. Enterococcus faecalis , Staphylococcus aureus (penicillinase-producing strains), Enterobacter species, Escherichia coli , Klebsiella species, Pseudomonas aeruginosa , Serratia species*, Bacteroides species including B. fragilis *

(6) Bone and joint infections. Enterococcus faecalis , Staphylococcus aureus (penicillinase-producing strains), Staphylococcus epidermidis , Enterobacter species, Pseudomonas aeruginosa

(7) Skin and skin structure infections. Enterococcus faecalis , Staphylococcus aureus (penicillinase-producing strains), 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*

(8) Endocarditis. Staphylococcus aureus (penicillinase-producing strains)

(9) Polymicrobic infections. Imipenem and Cilastatin for Injection (I.V.) is indicated for polymicrobic infections including those in which S. pneumoniae (pneumonia, septicemia), S. pyogenes (skin and skin structure), or nonpenicillinase-producing 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.

Imipenem and Cilastatin for Injection (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, Imipenem and Cilastatin for Injection (I.V.) is useful for the treatment of mixed infections and as presumptive therapy prior to the identification of the causative organisms.
__________________________________________________________________
* Efficacy for this organism in this organ system was studied in fewer than 10 infections.

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 Imipenem and Cilastatin for Injection (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 Imipenem and Cilastatin for Injection (I.V.).

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Imipenem and Cilastatin for Injection (I.V.) and other antibacterial drugs, Imipenem and Cilastatin for Injection (I.V.) should be used only to treat or prevent 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. 

IMIPENEM AND CILASTATIN CONTRAINDICATIONS

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

WARNINGS

SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC) REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING THERAPY WITH BETA-LACTAMS. THESE REACTIONS ARE MORE APT TO OCCUR IN PERSONS WITH A HISTORY OF SENSITIVITY TO MULTIPLE ALLERGENS.

THERE HAVE BEEN REPORTS OF PATIENTS 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 (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, IMIPENEM AND CILASTATIN FOR INJECTION (I.V.) 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 Imipenem and Cilastatin for Injection (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 Imipenem and Cilastatin for Injection (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 Imipenem and Cilastatin for Injection (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 Imipenem and Cilastatin for Injection (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 Imipenem and Cilastatin for Injection (I.V.) unless hemodialysis is instituted within 48 hours.

For patients on hemodialysis, Imipenem and Cilastatin for Injection (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 Imipenem and Cilastatin for Injection (I.V.) re-examined to determine whether it should be decreased or the antibiotic discontinued.

As with other antibiotics, prolonged use of Imipenem and Cilastatin for Injection (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 Imipenem and Cilastatin for Injection (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.

Information for Patients
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 co-administration with Imipenem and Cilastatin for Injection (I.V.). If treatment with Imipenem and Cilastatin for Injection (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 Imipenem and Cilastatin for Injection (I.V.)   should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Imipenem and Cilastatin for Injection (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 Imipenem and Cilastatin for Injection (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.

Laboratory Tests
While Imipenem and Cilastatin for Injection (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.

Drug Interactions
Generalized seizures have been reported in patients who received ganciclovir and Imipenem and Cilastatin for Injection (I.V.). These drugs should not be used concomitantly unless the potential benefits outweigh the risks. 

Since concomitant administration of Imipenem and Cilastatin for Injection (I.V.) 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 Imipenem and Cilastatin for Injection (I.V.).

Imipenem and Cilastatin for Injection (I.V.) should not be mixed with or physically added to other antibiotics. However, Imipenem and Cilastatin for Injection (I.V.) 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 ).

Carcinogenesis, Mutagenesis, Impairment of Fertility
Long term studies in animals have not been performed to evaluate carcinogenic potential of imipenem-cilastatin. 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^†† 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 times^†† 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 times^†† (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 to 4000 mg/day), caused body weight loss, diarrhea, and maternal deaths. When 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). When doses of imipenem-cilastatin sodium (approximately 100 mg/kg/day or approximately 0.6 times^†† 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. Imipenem and Cilastatin for Injection (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 Imipenem and Cilastatin for Injection (I.V.) is administered to a nursing woman.

Pediatric Use
Use of Imipenem and Cilastatin for Injection (I.V.) in pediatric patients, neonates to 16 years of age, is supported by evidence from adequate and well-controlled studies of Imipenem and Cilastatin for Injection (I.V.) in adults and by the following clinical studies and published literature in pediatric patients: Based on published studies of 178** pediatric patients ≥3 months of age (with non-CNS infections), the recommended dose of Imipenem and Cilastatin for Injection (I.V.) is 15 to 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 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. Based on studies in adults, the maximum daily dose for treatment of infections with fully susceptible organisms is 2 g per day, and of infections with moderately susceptible organisms (primarily some strains of P. aeruginosa ) is 4 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 135*** 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 to 4 wks of age: 25 mg/kg every 8 hrs
    4 wks to 3 mos. of age: 25 mg/kg every 6 hrs.

In a published 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 15 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.

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 impaired renal function, as no data are available.

Geriatric Use
Of the approximately 3600 subjects ≥18 years of age in clinical studies of Imipenem and Cilastatin for Injection (I.V.) , including postmarketing studies, approximately 2800 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 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 ).
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^†† Based on patient body surface area of 1.6 m² (weight of 60 kg).
** Two patients were less than 3 months of age.
*** One patient was greater than 3 months of age.

IMIPENEM AND CILASTATIN ADVERSE REACTIONS

Adults
Imipenem and Cilastatin for Injection (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 Imipenem and Cilastatin for Injection (I.V.).

Local Adverse Reactions
Adverse local clinical reactions that were reported as possibly, probably, or definitely related to therapy with Imipenem and Cilastatin for Injection (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 Imipenem and Cilastatin for Injection (I.V.) were nausea (2%), 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; 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 Imipenem and Cilastatin for Injection (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:

In studies of 135 patients (newborn to 3 months of age), the following adverse events were noted:

Examination of published literature and spontaneous adverse event reports suggested a similar spectrum of adverse events in adult and pediatric patients.

To report SUSPECTED ADVERSE EVENTS, contact FDA at 1-800-FDA-1088 or www.fda.gov.

OVERDOSAGE

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 to 56 minutes at all doses.

The acute intravenous toxicity of imipenem-cilastatin sodium was produced within 5 to 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 Imipenem and Cilastatin for Injection (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.

IMIPENEM AND CILASTATIN DOSAGE AND ADMINISTRATION

Adults
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. 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 Imipenem and Cilastatin for Injection (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.

Due to the high antimicrobial activity of Imipenem and Cilastatin for Injection (I.V.) , it is recommended that the maximum total daily dosage not exceed 50 mg/kg/day or 4 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 Imipenem and Cilastatin for Injection (I.V.) at doses up to 90 mg/kg/day in divided doses, not exceeding 4 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 Imipenem and Cilastatin for Injection (I.V.) as indicated in the tables below. Creatinine clearance may be calculated from serum creatinine concentration by the following equation:

To determine the dose for adults with impaired renal function and/or reduced body weight:
1. Choose a total daily dose from Table 3 based on infection characteristics.
2. a) If the total daily dose is 1 g, 1.5 g, or 2 g, use the appropriate subsection of Table 4 and continue with step 3.
    b) If the total daily dose is 3 g or 4 g, use the appropriate subsection of Table 5 and continue with step 3.
3. From Table 4 or 5:
    a) Select the body weight on the far left which is closest to the patient's body weight (kg).
    b) Select the patient's creatinine clearance category.
    c) Where the row and column intersect is the reduced dosage regimen.

Patients with creatinine clearances of 6 to 20 mL/min/1.73 m² should be treated with Imipenem and Cilastatin for Injection (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 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.

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 to 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 Imipenem and Cilastatin for Injection (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, Imipenem and Cilastatin for Injection (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 to 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 g per day, and of infections with moderately susceptible organisms (primarily some strains of P . aeruginosa ) is 4 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 to 4 wks of age: 25 mg/kg every 8 hrs
    4 wks to 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.

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 impaired renal function, as no data are available.  

PREPARATION OF SOLUTION

After constitution it is to be solubilized in a suitable parenteral fluid prior to intravenous infusion.

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 Imipenem and Cilastatin for Injection (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.

COMPATIBILITY AND STABILITY

Before Reconstitution:
The dry powder should be stored at 20 to 25°C (68 to 77°F) [See USP Controlled Room Temperature.]

Reconstituted Solutions:
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.

Imipenem and Cilastatin for Injection (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 Imipenem and Cilastatin for Injection (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%

Imipenem and Cilastatin for Injection (I.V.) should not be mixed with or physically added to other antibiotics. However, Imipenem and Cilastatin for Injection (I.V.) may be administered concomitantly with other antibiotics, such as aminoglycosides.

HOW SUPPLIED

Imipenem and Cilastatin for Injection (I.V.) is supplied as a sterile powder mixture in single dose vials containing imipenem (anhydrous equivalent) and cilastatin sodium as follows:

*250 mg imipenem equivalent and 250 mg cilastatin equivalent and 10 mg sodium bicarbonate as a buffer.
^†500 mg imipenem equivalent and 500 mg cilastatin equivalent and 20 mg sodium bicarbonate as a buffer.

REFERENCES

• Clinical and Laboratory Standards (CLSI). Methods for Dilution Antimicrobial   Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard  - 9^th ed. CLSI document M07-A9. CLSI, 950 West Valley Rd., Suite 2500, Wayne, PA 19087, 2012.
• CLSI. Performance Standards for Antimicrobial Susceptibility Testing; 22^nd Informational Supplement. CLSI document M100-S22, 2012.
• CLSI. Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard  - 11^th ed. CLSI document M02-A11, 2012.
• CLSI. Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard  - 8^th ed. CLSI document M11-A8, 2012.

Revised: October 2013

Made in India

EN-3354

948026299

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                                         Manufactured for: Hospira, Inc. 
                                          Lake Forest, IL 60045, USA.
 

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