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Imipenem and Cilastatin (Systemic)


VA CLASSIFICATION
Primary: AM119

Commonly used brand name(s): Primaxin; Primaxin IM; Primaxin IV.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antibacterial (systemic)—

Indications

General considerations
Imipenem is the first of a class of beta-lactam antibiotics called carbapenems. It has a very wide spectrum of activity in vitro , including most gram-positive and gram-negative aerobic and anaerobic bacteria. It is also stable in the presence of bacterial beta-lactamases. Imipenem is administered with an equal amount of cilastatin, a renal dehydropeptidase inhibitor that blocks the renal metabolism of imipenem and increases its urinary recovery. Cilastatin has no antibacterial activity or effect on beta-lactamases, and does not potentiate or antagonize the effects of imipenem. {03} {37}

Imipenem has excellent in vitro activity against aerobic gram-positive organisms, including most strains of staphylococci, streptococci, and some enterococci. Exceptions to this include Enterococcus faecium , which is usually resistant, and an increasing number of strains of methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci. {03} {37} {38} {48}

Imipenem also has excellent in vitro activity against most species of Enterbacteriaceae, including Escherichia coli , Klebsiella species, Citrobacter sp., Morganella morganii , and Enterobacter sp. It is slightly less potent in vitro against Serratia marcescens , Proteus mirabilis , indole-positive Proteus sp., and Providencia stuartii . Most strains of Pseudomonas aeruginosa are susceptible; however, increasing resistance has been seen in patients receiving imipenem who have advanced, refractory infections. Many strains of Ps. cepacia and virtually all strains of Xanthamonas maltophilia are resistant. {37} {38} {48}

Most anaerobic species are inhibited by imipenem, including Bacteroides sp., Fusobacterium sp., and Clostridium sp. However, C. difficile is only moderately susceptible. Other susceptible organisms in vitro include Campylobacter sp., Haemophilus influenzae , Neisseria gonorrhoeae , including penicillinase-producing strains, Yersinia enterocolitica , Nocardia asteroides , and Legionella sp. Chlamydia trachomatis is resistant to imipenem. {03} {37} {48}

Accepted

Bone and joint infections (treatment)—Intravenous imipenem and cilastatin combination is indicated in the treatment of bone and joint infections caused by susceptible organisms.

Endocarditis, bacterial (treatment)—Intravenous imipenem and cilastatin combination is indicated in the treatment of bacterial endocarditis caused by susceptible organisms.

Intra-abdominal infections (treatment)—Intravenous and intramuscular imipenem and cilastatin combination is indicated in the treatment of intra-abdominal infections caused by susceptible organisms.

Pelvic infections, female (treatment)—Intravenous and intramuscular imipenem and cilastatin combination is indicated in the treatment of female pelvic infections caused by susceptible organisms.

Pneumonia, bacterial (treatment)—Intravenous and intramuscular imipenem and cilastatin combination is indicated in the treatment of bacterial pneumonia caused by susceptible organisms.

Septicemia, bacterial (treatment)—Intravenous imipenem and cilastatin combination is indicated in the treatment of bacterial septicemia caused by susceptible organisms.

Skin and soft tissue infections (treatment)—Intravenous and intramuscular imipenem and cilastatin combination is indicated in the treatment of skin and soft tissue infections caused by susceptible organisms.

Urinary tract infections, bacterial (treatment)— Intravenous imipenem and cilastatin combination is indicated in the treatment of bacterial urinary tract infections caused by susceptible organisms.

[Melioidosis (treatment)]1—Intravenous imipenem and cilastatin combination is indicated for the treatment of melioidosis{59}{60}{61}{62}{63}{64}{65}{66}.
—Melioidosis is an infection with Burkholdria pseudomallei, previously known as Pseudomonas pseudomallei. It is endemic in areas of southeast Asia and the northern part of Australia. Melioidosis causes acute and chronic pulmonary disease, abscesses of the skin and internal organs, meningitis, brain abscess and cerebritis, and acute fulminant rapidly fatal sepsis. Infection with B. pseudomallei has a high mortality rate. It is more common among adults, individuals with diabetes, and individuals with chronic renal disease, but it can occur in normal hosts and children. Melioidosis can reactivate years after primary infection and result in chronic or acute life-threatening disease. Melioidosis should be considered as a potential diagnosis for any patient with exposure to areas of endemicity{59}{60}{61}{62}{63}{64}{65}{66}.

[Neutropenia, febrile (treatment) ]1—Intravenous imipenem and cilastatin combination is indicated for empiric treatment of febrile neutropenia{49}{50}{51}{52}{53}{54}{55}{56}{57}{58}.
—In patients at high risk of severe infection, including patients with a history of recent bone marrow transplantation, with hypotension at presentation, with an underlying hematologic malignancy, or with severe or prolonged neutropenia, antimicrobial therapy alone may not be appropriate{49}{50}{51}{52}{53}{54}{55}{56}{57}{58}.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Imipenem: 317.36 {45}
    Cilastatin sodium: 380.43 {44}

pKa at 25 °C (77 °F)—


Imipenem {25}:
    pKa 1—3.2
    pKa 2—9.9



Cilastatin sodium (with aqueous sodium hydroxide) {25}:
    pKa 1—2.0
    pKa 2—4.4
    pKa 3—9.2


Mechanism of action/Effect:

Imipenem—Bactericidal {01} {04} {05} {10} {15} {16} {22} {31}; binds to penicillin-binding proteins (PBP) 1A, 1B, 2, 4, 5, and 6 of E. coli {01} {03} {04} {05} {08} {10} {16} {27} and to PBP 1A, 1B, 2, 4, and 5 of Ps. aeruginosa {01} {04} {05} {08} {10} {16} {27}; this results in inhibition of bacterial cell wall synthesis {01} {05} {10} {16} {17} {20} {25}; imipenem apparently has greatest affinity for PBP 1A, 1B, and 2, and the least affinity for PBP 3 {03} {04} {05} {08} {10} {16}; imipenem's ability to bind to bacterial PBP 2 causes development of small spheres or ellipsoids without formation of filaments commonly seen with penicillins and cephalosporins {05} {08} {10} {16} {25}, ultimately resulting in lysis and death; its lethal effect may also be related to binding to PBP 1A and 1B as well {01} {03} {08}; imipenem is highly resistant to degradation by bacterial beta-lactamases {03} {06} and may demonstrate a ``post-antibiotic'' effect in some bacteria {10} {11}.

Cilastatin—A competitive, reversible, highly specific inhibitor of the renal dipeptidase, dehydropeptidase I (DHP I) {01} {09} {10} {12} {17} {18} {20} {22} {23} {24} {29} {31} {32}; cilastatin blocks tubular secretion of imipenem by competitive exclusion at its transport site {12} {25} {32}, thereby preventing the renal metabolism of imipenem {01} {02} {03} {05} {06} {08} {09} {10} {17} and resulting in significantly improved urinary recovery of imipenem {08} {10} {17} {18} {20} {25} {32}; cilastatin may also prevent proximal renal tubular necrosis that occurs when imipenem is used alone {05} {08} {09} {10} {25}; cilastatin does not inhibit bacterial beta-lactamases {05} and has no intrinsic antibacterial activity. {02} {05} {08} {10} {29}

Absorption:


Bioavailability:


Intramuscular {47}

Imipenem—95%.

Cilastatin—75%.



Distribution:

Imipenem rapidly and widely distributed to most tissues and fluids {03} {25}; distributed to sputum, pleural fluid, peritoneal fluid, interstitial fluid, bile, aqueous humor, reproductive organs, and bone {01} {03} {29}; highest concentrations found in pleural fluid, interstitial fluid, peritoneal fluid, and reproductive organs {01}; low concentrations have been detected in the cerebrospinal fluid (CSF) {03} {29}.


Vol D:

Neonates: 0.4 to 0.5 L/kg. {04} {29}

Children (2 to 12 years old): Approximately 0.7 L/kg. {17}

Adults: 0.23 to 0.31 L/kg. {37}


Protein binding:

Imipenem—Low (20%). {01} {02} {10} {42}

Cilastatin—Moderate (40%). {01} {42}

Biotransformation:

Imipenem—Renal; when given alone, imipenem is metabolized in the kidneys by hydrolysis of the beta-lactam ring {02} {03} {05} {08} {10} {12} {17} {20} {24} {27} {32} caused by the renal dipeptidase, dehydropeptidase I (DHP I), resulting in low urinary concentrations {01} {02} {04} {05} {06} {08} {09} {10} {12} {17} {18} {20} {24} {25} {32} {34}; DHP I is an enzyme located on the brush border of the proximal renal tubular epithelium {03} {04} {06} {08} {09} {10} {12} {13} {17} {18} {20} {24} {25} {27} {32}; DHP I acts only after imipenem has been cleared from the plasma by glomerular filtration or tubular secretion (``post-excretory'' metabolism) {03} {10} {25}; metabolism occurs only in the tubular cell or glomerular filtrate {24} {25}; virtually all of the secreted fraction and approximately 75% of the filtered fraction are metabolized (a total of 60 to 95%). {25}

Cilastatin—Metabolized to N-acetyl conjugate. {05}

Half-life:


Adults:


Intravenous—


Normal renal function {01} {02} {03} {05} {08} {27} {32} {34}

Imipenem: Approximately 1 hour.

Cilastatin: Approximately 1 hour.



Impaired renal function {03} {08} {25} {32} {34}

Imipenem: 2.9 to 4.0 hours.

Cilastatin: 13.3 to 17.1 hours.




Intramuscular—


Normal renal function—

Imipenem: 2 to 3 hours. {47}





Neonates:


Intravenous {04} {08} {29}

Imipenem—1.7 to 2.4 hours.

Cilastatin—3.8 to 8.4 hours.




Children (2 to 12 years of age):

Intravenous: 1 to 1.2 hours. {08} {17}


Time to peak concentration:


Intramuscular {47}:

Imipenem: Within 2 hours.

Cilastatin: Within 1 hour.


Peak serum concentration:


Imipenem:

Intravenous: Approximately 14 to 24, 21 to 58, and 41 to 83 mcg per mL following a dose of 250 mg, 500 mg, and 1 gram, respectively, over 20 minutes. {01} {03} {08} {22} {27} {34}

Intramuscular: Approximately 10 and 12 mcg per mL following a dose of 500 mg and 750 mg, respectively. {47}



Cilastatin:

Intravenous: Approximately 15 to 25, 31 to 49, and 56 to 80 mcg per mL following a dose of 250 mg, 500 mg, and 1 gram, respectively, over 20 minutes. {01} {03} {08} {22} {27}

Intramuscular: Approximately 24 and 33 mcg per mL following a dose of 500 mg and 750 mg, respectively. {47}


Urine concentration


Imipenem:

>10 mcg per mL up to 8 hours following a 500 mg intravenous dose. {01}

>10 mcg per mL for 12 hours following a 500 mg and 750 mg intramuscular dose. {47}


Elimination:


Imipenem alone—
        Renal; approximately 5 to 40% excreted in urine by both glomerular filtration {02} {03} {05} {10} {12} {25} {32} and tubular secretion {39}.



Cilastatin alone—
        Renal; approximately 70 to 78% excreted in urine within 10 hours, by both glomerular filtration and tubular secretion. {01} {03} {05} {12} {24} {32}
        Dialysis: Substantial amounts (approximately 40 to 82%) rapidly cleared from the blood by hemodialysis. {01} {03} {25} {32} {34}



Imipenem with cilastatin—
        Renal; approximately 70 to 76% excreted in urine within 10 hours, by both glomerular filtration and active tubular secretion (approximately two-thirds of that amount by glomerular filtration and one-third by tubular secretion); no further urinary excretion detectable. {01} {02} {03} {05} {08} {10} {18} {25} {27}
        Nonrenal; approximately 20 to 25% excreted by unknown nonrenal mechanism {03} {10} {18}, possibly including up to 1 to 2% excreted via the bile in the feces. {03} {05} {12} {33}
        Dialysis: Substantial amounts (approximately 73 to 90%) rapidly cleared from the blood by hemodialysis. {01} {03} {25} {32} {34} A 3-hour session of intermittent hemofiltration has removed approximately 75% of a given dose. {26}



Precautions to Consider

Cross-sensitivity and/or related problems

Patients allergic to other beta-lactam antibacterials (e.g., penicillins, cephalosporins) may be allergic to imipenem also. {01} {03} {07}

Although imipenem has been administered without incident to some patients with rash-type penicillin allergy, caution is recommended when imipenem is administered to patients with a history of penicillin anaphylaxis because of cross-reactivity. {35} {46}

Carcinogenicity/Mutagenicity

Gene toxicity studies such as the V79 mammalian cell mutation assay, Ames test, unscheduled DNA synthesis assay, and in vivo mouse cytogenicity test have shown no evidence of genetic damage with imipenem and cilastatin combination. {01} {25} {47}

Pregnancy/Reproduction

Pregnancy—
Studies in humans have not been done.

Studies in mice, rats, and rabbits given doses ranging from the usual human dose up to 33 times the usual human dose have not shown that imipenem, cilastatin, or the combination causes adverse effects on the fetus. {01} Studies in pregnant cynomolgus monkeys given intravenous bolus doses of 40 mg per kg of body weight (mg/kg) per day or 160 mg/kg per day subcutaneously resulted in maternal toxicity, including emesis, inappetence, weight loss, diarrhea, abortion, and death. No significant toxicity was observed when non-pregnant cynomolgus monkeys were given subcutaneous doses of up to 180 mg/kg per day. When doses of 100 mg/kg per day 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 teratogenicity, but an increase in embryonic loss relative to the control groups. {47}

FDA Pregnancy Category C.

Breast-feeding

It is not known whether imipenem or cilastatin is distributed into breast milk. However, problems in humans have not been documented. {01} {03}

Pediatrics

The half-life of imipenem in neonates is longer (1.7 to 2.4 hours) than that in adults with normal renal function (approximately 1 hour). The half-life in older pediatric patients (2 to 12 years of age) is 1 to 1.2 hours.

The half-life of cilastatin in neonates is longer (3.8 to 8.4 hours) than that in adults with normal renal function (approximately 1 hour). {08} {17} {29}

Appropriate studies have not been performed in children up to 12 years of age. {42} {47}


Geriatrics


No information is available on the relationship of age to the effects of imipenem and cilastatin combination in geriatric patients. However, elderly patients are more likely to have an age-related decrease in renal function, which may require a reduction of dosage in patients receiving imipenem and cilastatin.


Dental

Imipenem and cilastatin may cause glossitis (inflammation of the tongue), tongue papillar hypertrophy, and increased salivation. {42}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Probenecid{01}{03}{05}{08}{18}{24}    (since concurrent use of probenecid results in only minimal increases in the serum concentrations and half-life of imipenem, concurrent use is not recommended where higher imipenem serum concentrations may be desirable)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Positive direct antiglobulin (Coombs') tests    (may occur during therapy {01} {03} {07} {09})

With physiology/laboratory test values
» Alanine aminotransferase (ALT [SGPT]), serum and
» Alkaline phosphatase, serum and
» Aspartate aminotransferase (AST [SGOT]), serum and
Lactate dehydrogenase (LDH), serum    (values may be transiently increased)


Bilirubin, serum and
Blood urea nitrogen (BUN) concentrations and
Creatinine, serum    (concentrations may be transiently increased {01} {03} {07} {08} {09} {12} {18})


Hematocrit (HCT) and
Hemoglobin (Hb) concentrations    (may be decreased {01} {18})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Allergy to imipenem, cilastatin, or other beta-lactams (penicillin, cephalosporins){35}{42}
» Central nervous system (CNS) disorders (e.g., brain lesions or history of seizures)    (seizures are more likely to occur in patients receiving higher doses of imipenem, or in patients with CNS lesions, a history of seizure disorders, or renal function impairment {01} {03} {08} {09} {18} {36})


» Renal function impairment{01}{03}{08}{18}{42}    (because imipenem and cilastatin are primarily excreted through the kidneys, this medicine must be administered in a reduced dosage to patients with impaired renal function)




Side/Adverse Effects

Note: The following side/adverse effects of imipenem and cilastatin combination are similar in nature and incidence to those of other beta-lactam antibacterials. However, the incidence of seizures is higher than that seen with other beta-lactam antibiotics; it is reported to be 1.5 to 2%. The risk of seizures increases in patients receiving more than 2 grams of imipenem per day, those with a pre-existing seizure disorder, and patients with decreased renal function. {07} {08} {09} {36}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Allergic reactions (fever; hives; itching; skin rash; wheezing){01}{03}{07}{08}{09}{12}{13}{19}{35}
    
CNS toxicity (confusion; dizziness; seizures; tremors){01}{03}{07}{08}{09}{18}{25}{36}
    
thrombophlebitis (pain at site of injection){42}

Incidence less frequent
    
Infusion rate reaction (dizziness; nausea and vomiting; sweating; unusual tiredness or weakness)—occurs with too rapid an infusion rate{01}{03}{07}{08}{09}{12}{13}{18}{19}{23}{24}{25}{27}{31}

Incidence rare
    
Pseudomembranous colitis (abdominal or stomach cramps and pain, severe; diarrhea, watery and severe, which may also be bloody; fever){01}{03}{07}{09}{25}{33}



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Gastrointestinal disturbances (diarrhea; nausea and vomiting){43}



Those indicating the need for medical attention if they occur after medication is discontinued {01} {03} {07} {09} {25} {33}
    
Pseudomembranous colitis (severe abdominal or stomach cramps and pain; watery and severe diarrhea, which may also be bloody; fever)




Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Imipenem and Cilastatin (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Allergy to imipenem or cilastatin; patients allergic to other beta-lactams may also be allergic to imipenem





Dental—Imipenem and cilastatin may cause glossitis, tongue papillar hypertrophy, and increased salivation
Other medical problems, especially CNS disorders or renal function impairment

Proper use of this medication
» Importance of receiving medication for full course of therapy and on regular schedule

» Proper dosing

Precautions while using this medication
» Continuing anticonvulsant therapy in patients with a history of seizures

» For severe diarrhea, checking with physician before taking any antidiarrheals; for mild diarrhea, taking kaolin- or attapulgite-containing, but not other, antidiarrheals; checking with physician or pharmacist if mild diarrhea continues or worsens


Side/adverse effects
Signs of potential side effects, especially allergic reactions, CNS toxicity, infusion rate reaction, pseudomembranous colitis, and thrombophlebitis


General Dosing Information
Intravenous doses of 250 or 500 mg of imipenem should be given over a 20- to 30-minute period in adults. Doses of 1 gram should be given over a 40- to 60-minute period. {01} {12} {22} {23} {24} {25} {34} In pediatric patients, imipenem may be administered over a 20- to 30-minute period. {09} {17} {20} {29}

Intramuscular imipenem and cilastatin combination should be administered by deep IM injection into a large muscle mass, such as the gluteal muscles or lateral part of the thigh. {47}

In patients receiving more than 2 grams of imipenem per day, there is an increased risk of seizures. {03}

If a dose of this medication is missed, give it as soon as possible. However, if it is almost time for the next dose, skip the missed dose and go back to the regular dosing schedule. Do not double doses.

For treatment of adverse effects
Anticonvulsants should be continued in the treatment of patients receiving imipenem and cilastatin combination who have known seizure disorders. In patients who develop symptoms of CNS toxicity (e.g., focal tremors, myoclonus, or seizures) during treatment with imipenem, anticonvulsant therapy (e.g., phenytoin or benzodiazepines) should be initiated, and the dosage of imipenem should be reduced or the drug should be discontinued. {01} {03} {07}

If an allergic reaction to imipenem and cilastatin combination occurs, the drug should be discontinued. Severe hypersensitivity reactions may require the administration of epinephrine or other emergency measures. {40}

Some patients may develop nausea, vomiting, hypotension, dizziness, or sweating during administration of imipenem and cilastatin combination, especially after rapid infusion. If these symptoms develop, the rate of infusion should be slowed. If this is not effective, it may be necessary to discontinue the drug. {01} {03} {07} {09} {19} {23}


For antibiotic-associated pseudomembranous colitis (AAPMC):
Some patients may develop AAPMC, caused by Clostridium difficile toxin, during or following administration of imipenem. Mild cases may respond to discontinuation of the drug alone. Moderate to severe cases may require fluid, electrolyte, and protein replacement.

In cases not responding to the above measures or in more severe cases, oral metronidazole, oral bacitracin, or oral vancomycin may be used. {39} Oral vancomycin is effective in doses of 125 to 500 mg every 6 hours for 5 to 10 days. The dose of metronidazole is 250 to 500 mg every 8 hours for 5 to 10 days. Recurrences may be treated with a second course of these medications. {39}

Cholestyramine and colestipol resins have been shown to bind C. difficile toxin in vitro . If cholestyramine or colestipol resin is administered in conjunction with oral vancomycin, the medications should be administered several hours apart since the resins have been shown to bind oral vancomycin also.

In addition, AAPMC may result in severe watery diarrhea which may occur during therapy or up to several weeks after therapy is discontinued. If diarrhea occurs, administration of antiperistaltic antidiarrheals is not recommended since they may delay the removal of toxins from the colon, thereby prolonging and/or worsening the diarrhea. {39}



Parenteral Dosage Forms

IMIPENEM AND CILASTATIN FOR INJECTION USP

Usual adult and adolescent dose
Antibacterial
Intravenous infusion, based on anhydrous imipenem content:

Mild infections—250 to 500 mg every six hours.

Moderate infections—500 mg every six to eight hours to 1 gram every eight hours.

Severe, life-threatening infections—500 mg every six hours to 1 gram every six to eight hours. {01} {02} {08} {12} {13} {18} {19} {23} {31}

Note: Lower doses are used in the treatment of infections caused by gram-positive organisms, anaerobes, and highly susceptible gram-negative organisms. Infections caused by other gram-negative organisms require higher doses.
Uncomplicated urinary tract infections: 250 mg every six hours.
Complicated urinary tract infections: 500 mg every six hours.
Adults with impaired renal function may require a reduction in dose as given below. Doses are based on an average body weight of 70 kg. Patients weighing less than 70 kg should receive a proportional reduction in dosage {01} {03} {06} {08} {09} {32} {34}.

Creatinine Clearance
(mL/min/1.73 M 2)/
(mL/sec)
Dose
>70/1.17
See Usual adult and adolescent dose
30–70/0.50–1.17
500 mg every 6 to 8 hours
20–30/0.33–0.50
500 mg every 8 to 12 hours
0–20/0–0.33
250 to 500 mg every 12 hours
Hemodialysis patients
Supplemental dose after hemodialysis, unless next dose scheduled within 4 hours



[Melioidosis ]1
Intravenous, 50 mg per kg of body weight daily{59}{60}{61}{62}{63}{64}{65}{66}.

Adults with impaired renal function may require a reduction in dose as indicated above{01} {03} {06} {08} {09} {32} {34}.

[Neutropenia, febrile]1
Intravenous, 500 mg every six hours to 1 gram every eight hours{49}{50}{51}{52}{53}{54}{55}{56}{57}{58}.

Adults with impaired renal function may require a reduction in dose as indicated above{01} {03} {06} {08} {09} {32} {34}.


Usual adult prescribing limits
Up to a maximum of 50 mg (imipenem) per kg of body weight or 4 grams daily, whichever is lower. {01} {03} {07} {08} {09} {18} {31}

Usual pediatric dose
Antibacterial or
[ Melioidosis or]1
[ Neutropenia, febrile]1
Infants and children up to 12 years of age: Dosage has not been established. {01}

Children 12 years of age and older: See Usual adult and adolescent dose .


Size(s) usually available:
U.S.—


250 mg (anhydrous imipenem) and 250 mg (cilastatin) (Rx) [Primaxin IV]


500 mg (anhydrous imipenem) and 500 mg (cilastatin) (Rx) [Primaxin IV]

Canada—


250 mg (anhydrous imipenem) and 250 mg (cilastatin) (Rx) [Primaxin]


500 mg (anhydrous imipenem) and 500 mg (cilastatin) (Rx) [Primaxin]

Packaging and storage:
Prior to reconstitution, store below 30 °C (86 °F), unless otherwise specified by manufacturer.

Preparation of dosage form:
To prepare initial dilution for intravenous infusion, add approximately 10 mL of diluent (see manufacturer's package insert) to each 250- or 500-mg vial (13-mL) and shake well. The resulting suspension should be transferred to not less than 100 mL of suitable intravenous fluids. Do not administer the initially prepared suspension intravenously. Add an additional 10 mL of diluent to each previously reconstituted vial and shake well. Transfer the remaining contents of the vial to the infusion container. Shake the resulting mixture well until clear. Do not administer a cloudy solution. {01} {25}

For reconstitution of piggyback infusion bottles (120-mL), add 100 mL of diluent (see manufacturer's package insert) to each 250- or 500-mg infusion bottle. Shake the resulting mixture well until clear. Do not administer a cloudy solution. {01}

Stability:
After reconstitution with sterile water for injection, solutions retain their potency for 8 hours at room temperature or for 48 hours if refrigerated at 4 °C (39 °F). {25}

After reconstitution with 0.9% sodium chloride injection, solutions retain their potency for 10 hours at room temperature or for 48 hours if refrigerated at 4 °C (39 °F). {01} {25}

After reconstitution with other diluents, solutions retain their potency for 4 hours at room temperature or for 24 hours if refrigerated at 4 °C (39 °F). {01} {25}

Solutions of imipenem and cilastatin combination should not be frozen. {01}

Solutions may vary from colorless to yellow in color; color changes within this range do not affect potency. {01} Imipenem and cilastatin combination may become slightly discolored under strong ultraviolet (UV) light. {25}

Incompatibilities:
Extemporaneous admixtures of beta-lactam antibacterials and aminoglycosides may result in substantial mutual inactivation. If they are administered concurrently, they should be administered in separate sites. Do not mix them in the same intravenous bag or bottle.


IMIPENEM AND CILASTATIN FOR INJECTABLE SUSPENSION USP

Usual adult and adolescent dose
Antibacterial
Intramuscular, mild to moderate infections: {47}

Female pelvic infections and

Pneumonia and

Skin and soft tissue infections—500 to 750 mg every twelve hours.

Intra-abdominal infections—750 mg every twelve hours.


Note: Safety and efficacy have not been studied in patients with a creatinine clearance of less than 20 mL/min.


Usual adult prescribing limits
Up to 1500 mg daily. {47}

Usual pediatric dose
Antibacterial
Infants and children up to 12 years of age: Dosage has not been established. {47}

Children 12 years of age and older: See Usual adult and adolescent dose .


Size(s) usually available:
U.S.—


500 mg (anhydrous imipenem) and 500 mg (cilastatin) (Rx) [Primaxin IM]


750 mg (anhydrous imipenem) and 750 mg (cilastatin) (Rx) [Primaxin IM]

Canada—
Not commercially available.

Packaging and storage:
Prior to reconstitution, store below 30 °C (86 °F), unless otherwise specified by manufacturer.

Preparation of dosage form:
To prepare initial dilution for intramuscular use, add 2 mL of 1% lidocaine injection (without epinephrine) to each 500-mg vial, or 3 mL of 1% lidocaine injection (without epinephrine) to each 750-mg vial.

Stability:
After reconstitution with 1% lidocaine injection, the suspension should be used within one hour.

Suspensions are white to light tan in color; variations of color within this range do not affect the potency.

Incompatibilities:
Intramuscular imipenem and cilastatin combination should not be mixed with or physically added to other antibiotics. However, it may be administered concomitantly, but at separate sites, with other antibiotics.



Revised: 08/09/2000



References
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