Imipenem and Cilastatin for Injection

Name: Imipenem and Cilastatin for Injection

Side effects

Adults

PRIMAXIN I.V. is generally well tolerated. Many of the 1,723 patients treated in clinical trials were severely ill and had multiple background diseases and physiological impairments, making it difficult to determine causal relationship of adverse experiences to therapy with PRIMAXIN I.V.

Local Adverse Reactions

Adverse local clinical reactions that were reported as possibly, probably, or definitely related to therapy with PRIMAXIN I.V. were:

Phlebitis/thrombophlebitis — 3.1%
Pain at the injection site — 0.7%
Erythema at the injection site — 0.4%
Vein induration — 0.2%
Infused vein infection — 0.1%

Systemic Adverse Reactions

The most frequently reported systemic adverse clinical reactions that were reported as possibly, probably, or definitely related to PRIMAXIN I.V. were nausea (2.0%), diarrhea (1.8%), vomiting (1.5%), rash (0.9%), fever (0.5%), hypotension (0.4%), seizures (0.4%) (see PRECAUTIONS), dizziness (0.3%), pruritus (0.3%), urticaria (0.2%), somnolence (0.2%).

Additional adverse systemic clinical reactions reported as possibly, probably, or definitely drug related occurring in less than 0.2% of the patients or reported since the drug was marketed are listed within each body system in order of decreasing severity: Gastrointestinal — pseudomembranous colitis (the onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment, see WARNINGS), hemorrhagic colitis, hepatitis (including fulminant hepatitis), hepatic failure, jaundice, gastroenteritis, abdominal pain, glossitis, tongue papillar hypertrophy, staining of the teeth and/or tongue, heartburn, pharyngeal pain, increased salivation; Hematologic — pancytopenia, bone marrow depression, thrombocytopenia, neutropenia, leukopenia, hemolytic anemia; CNS — encephalopathy, tremor, confusion, myoclonus, paresthesia, vertigo, headache, psychic disturbances including hallucinations, dyskinesia, agitation; Special Senses — hearing loss, tinnitus, taste perversion; Respiratory — chest discomfort, dyspnea, hyperventilation, thoracic spine pain; Cardiovascular — palpitations, tachycardia; Skin — Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, angioneurotic edema, flushing, cyanosis, hyperhidrosis, skin texture changes, candidiasis, pruritus vulvae; Body as a whole — polyarthralgia, asthenia/weakness, drug fever; Renal — acute renal failure, oliguria/anuria, polyuria, urine discoloration. The role of PRIMAXIN I.V. in changes in renal function is difficult to assess, since factors predisposing to pre-renal azotemia or to impaired renal function usually have been present.

Adverse Laboratory Changes

Adverse laboratory changes without regard to drug relationship that were reported during clinical trials or reported since the drug was marketed were:

Hepatic: Increased ALT (SGPT), AST (SGOT), alkaline phosphatase, bilirubin, and LDH

Hemic: Increased eosinophils, positive Coombs test, increased WBC, increased platelets, decreased hemoglobin and hematocrit, agranulocytosis, increased monocytes, abnormal prothrombin time, increased lymphocytes, increased basophils

Electrolytes: Decreased serum sodium, increased potassium, increased chloride

Renal: Increased BUN, creatinine

Urinalysis: Presence of urine protein, urine red blood cells, urine white blood cells, urine casts, urine bilirubin, and urine urobilinogen.

Pediatric Patients

In studies of 178 pediatric patients ≥ 3 months of age, the following adverse events were noted:

The Most Common Clinical Adverse Experiences Without Regard to Drug Relationship (Patient Incidence > 1%)

Adverse Experience No. of Patients (%)
Digestive System
  Diarrhea 7* (3.9)
  Gastroenteritis 2 (1.1)
  Vomiting 2* (1.1)
Skin
  Rash 4 (2.2)
  Irritation, I.V. site 2 (1.1)
Urogenital System
  Urine discoloration 2 (1.1)
Cardiovascular System
  Phlebitis 4 (2.2)
*One patient had both vomiting and diarrhea and is counted in each category.

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

The Most Common Clinical Adverse Experiences Without Regard to Drug Relationship (Patient Incidence > 1%)

Adverse Experience No. of Patients (%)
Digestive System
  Diarrhea 4 (3.0%)
  Oral Candidiasis 2 (1.5%)
Skin
  Rash 2 (1.5%)
Urogenital System
  Oliguria/anuria 3 (2.2%)
Cardiovascular System
  Tachycardia 2 (1.5%)
Nervous System
  Convulsions 8 (5.9%)

Patients ( ≥ 3 Months of Age) With Normal Pretherapy but Abnormal During Therapy Laboratory Values

Laboratory Parameter Abnormality No. of Patients With Abnormalities/ No. of Patients With Lab Done (%)
Hemoglobin Age
< 5 mos.: < 10 gm %
6 mos.-12 yrs.: < 11.5 gm %
19/129 (14.7)
Hematocrit Age
< 5 mos.: < 30 vol %
6 mos.-12 yrs.: < 34.5 vol %
23/129 (17.8)
Neutrophils ≤ 1000/mm³ (absolute) 4/123 (3.3)
Eosinophils ≥ 7% 15/117 (12.8)
Platelet Count ≥ 500 ths/mm³ 16/119 (13.4)
Urine Protein ≥ 1 8/97 (8.2)
Serum Creatinine > 1.2 mg/dL 0/105 (0)
BUN > 22 mg/dL 0/108 (0)
AST (SGOT) > 36 IU/L 14/78 (17.9)
ALT (SGPT) > 30 IU/L 10/93 (10.8)

Patients ( < 3 Months of Age) With Normal Pretherapy but Abnormal During Therapy Laboratory Values

Laboratory Parameter No. of Patients With Abnormalities* (%)
Eosinophil Count↑ 11 (9.0%)
Hematocrit↓ 3 (2.0%)
Hematocrit↑ 1 (1.0%)
Platelet Count↑ 5 (4.0%)
Platelet Count↓ 2 (2.0%)
Serum Creatinine↑ 5 (5.0%)
Bilirubin↑ 3 (3.0%)
Bilirubin↓ 1 (1.0%)
AST (SGOT)↑ 5 (6.0%)
ALT (SGPT)↑ 3 (3.0%)
Serum Alkaline Phosphate↑ 2 (3.0%)
*The denominator used for percentages was the number of patients for whom the test was performed during or posttreatment and, therefore, varies by test.

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

Warnings

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

THERE HAVE BEEN REPORTS OF PATIENTS W ITH A HISTORY OF PENICILLIN HYPERSENSITIVITY W HO HAVE EXPERIENCED SEVERE HYPERSENSITIVITY REACTIONS W HEN TREATED W ITH ANOTHER BETA-LACTAM. BEFORE INITIATING THERAPY W ITH PRIMAXIN I.V., CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OTHER BETA-LACTAMS, AND OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, PRIMAXIN SHOULD BE DISCONTINUED.

SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS, AND AIRWAY MANAGEMENT, INCLUDING INTUBATION, MAY ALSO BE ADMINISTERED AS INDICATED.

Seizure Potential

Seizures and other CNS adverse experiences, such as confusional states and myoclonic activity, have been reported during treatment with PRIMAXIN I.V. (See PRECAUTIONS and ADVERSE REACTIONS.)

Case reports in the literature have shown that co-administration of carbapenems, including imipenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. Increasing the dose of valproic acid or divalproex sodium may not be sufficient to overcome this interaction. The concomitant use of imipenem and valproic acid/divalproex sodium is generally not recommended. Anti-bacterials other than carbapenems should be considered to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium. If administration of PRIMAXIN I.V. is necessary, supplemental anticonvulsant therapy should be considered (see PRECAUTIONS: DRUG INTERACTIONS).

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including PRIMAXIN I.V., and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD.

Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Clinical pharmacology

Adults

Intravenous Administration

Intravenous infusion of PRIMAXIN I.V. over 20 minutes results in peak plasma levels of imipenem antimicrobial activity that range from 14 to 24 μg/mL for the 250 mg dose, from 21 to 58 μg/mL for the 500 mg dose, and from 41 to 83 μg/mL for the 1000 mg dose. At these doses, plasma levels of imipenem antimicrobial activity decline to below 1 μg/mL or less in 4 to 6 hours. Peak plasma levels of cilastatin following a 20-minute intravenous infusion of PRIMAXIN I.V. range from 15 to 25 μg/mL for the 250 mg dose, from 31 to 49 μg/mL for the 500 mg dose, and from 56 to 88 μg/mL for the 1000 mg dose.

The plasma half-life of each component is approximately 1 hour. The binding of imipenem to human serum proteins is approximately 20% and that of cilastatin is approximately 40%. Approximately 70% of the administered imipenem is recovered in the urine within 10 hours after which no further urinary excretion is detectable. Urine concentrations of imipenem in excess of 10 μg/mL can be maintained for up to 8 hours with PRIMAXIN I.V. at the 500-mg dose. Approximately 70% of the cilastatin sodium dose is recovered in the urine within 10 hours of administration of PRIMAXIN I.V.

No accumulation of imipenem/cilastatin in plasma or urine is observed with regimens administered as frequently as every 6 hours in patients with normal renal function.

In healthy elderly volunteers (65 to 75 years of age with normal renal function for their age), the pharmacokinetics of a single dose of imipenem 500 mg and cilastatin 500 mg administered intravenously over 20 minutes are consistent with those expected in subjects with slight renal impairment for which no dosage alteration is considered necessary. The mean plasma half-lives of imipenem and cilastatin are 91 ± 7.0 minutes and 69 ± 15 minutes, respectively. Multiple dosing has no effect on the pharmacokinetics of either imipenem or cilastatin, and no accumulation of imipenem/cilastatin is observed.

Imipenem, when administered alone, is metabolized in the kidneys by dehydropeptidase I resulting in relatively low levels in urine. Cilastatin sodium, an inhibitor of this enzyme, effectively prevents renal metabolism of imipenem so that when imipenem and cilastatin sodium are given concomitantly, fully adequate antibacterial levels of imipenem are achieved in the urine.

After a 1 gram dose of PRIMAXIN I.V., the following average levels of imipenem were measured (usually at 1 hour post dose except where indicated) in the tissues and fluids listed:

Tissue or Fluid N Imipenem Level μg/mL or μg/g Range
Vitreous Humor 3 3.4 (3.5 hours post dose) 2.88-3.6
Aqueous Humor 5 2.99 (2 hours post dose) 2.4-3.9
Lung Tissue 8 5.6 (median) 3.5-15.5
Sputum 1 2.1
Pleural 1 22.0
Peritoneal 12 23.9 S.D.+5.3 (2 hours post dose)
Bile 2 5.3 (2.25 hours post dose) 4.6-6.0
CSF (uninflamed) 5 1.0 (4 hours post dose) 0.26-2.0
CSF (inflamed) 7 2.6 (2 hours post dose) 0.5-5.5
Fallopian Tubes 1 13.6
Endometrium 1 11.1
Myometrium 1 5.0
Bone 10 2.6 0.4-5.4
Interstitial Fluid 12 16.4 10.0-22.6
Skin 12 4.4 NA
Fascia 12 4.4 NA

Imipenem-cilastatin sodium is hemodialyzable. However, usefulness of this procedure in the overdosage setting is questionable. (See OVERDOSAGE.)

Microbiology

The bactericidal activity of imipenem results from the inhibition of cell wall synthesis. Its greatest affinity is for penicillin binding proteins (PBPs) 1A, 1B, 2, 4, 5 and 6 of Escherichia coli, and 1A, 1B, 2, 4 and 5 of Pseudomonas aeruginosa. The lethal effect is related to binding to PBP 2 and PBP 1B.

Imipenem has a high degree of stability in the presence of beta-lactamases, both penicillinases and cephalosporinases produced by gram-negative and gram-positive bacteria. It is a potent inhibitor of betalactamases from certain gram-negative bacteria which are inherently resistant to most beta-lactam antibiotics, e.g., Pseudomonas aeruginosa, Serratia spp., and Enterobacter spp.

Imipenem has in vitro activity against a wide range of gram-positive and gram-negative organisms. Imipenem has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections treated with the intravenous formulation of imipenem-cilastatin sodium as described in the INDICATIONS AND USAGE section.

Gram-positive Aerobes

Enterococcus faecalis (formerly S. faecalis)
(NOTE: Imipenem is inactive in vitro against Enterococcus faecium [formerly S. faecium].) Staphylococcus aureus including penicillinase-producing strains
Staphylococcus epidermidis
including penicillinase-producing strains
(NOTE: Methicillin-resistant staphylococci should be reported as resistant to imipenem.)
Streptococcus agalactiae
(Group B streptococci)
Streptococcus pneumoniae

Streptococcus pyogenes

Gram-negative Aerobes

Acinetobacter spp.
Citrobacter
spp.
Enterobacter
spp.
Escherichia coli

Gardnerella vaginalis

Haemophilus influenzae

Haemophilus parainfluenzae

Klebsiella
spp.
Morganella morganii

Proteus vulgaris

Providencia rettgeri

Pseudomonas aeruginosa

(NOTE: Imipenem is inactive in vitro against Stenotrophomonas [formerly Xanthomonas, formerly Pseudomonas] maltophilia and some strains of Burkholderia cepacia.)
Serratia spp., including S. marcescens

Gram-positive Anaerobes

Bifidobacterium spp.
Clostridium
spp.
Eubacterium
spp.
Peptococcus
spp.
Peptostreptococcus
spp.
Propionibacterium
spp.

Gram-negative Anaerobes

Bacteroides spp., including B. fragilis
Fusobacterium spp.

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

Imipenem exhibits in vitro minimum inhibitory concentrations (MICs) of 4 μg/mL or less against most ( ≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of imipenem in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Gram-positive Aerobes

Bacillus spp.
Listeria monocytogenes
Nocardia
spp.
Staphylococcus saprophyticus

Group C streptococci
Group G streptococci
Viridans group streptococci

Gram-negative Aerobes

Aeromonas hydrophila
Alcaligenes
spp.
Capnocytophaga
spp.
Haemophilus ducreyi

Neisseria gonorrhoeae
including penicillinase-producing strains
Pasteurella
spp.
Providencia stuartii

Gram-negative Anaerobes

Prevotella bivia
Prevotella disiens
Prevotella melaninogenica
Veillonella spp.

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

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide to the physician the results of in vitro susceptibility tests for antimicrobial drug products used in resident hospitals as periodic reports which describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a broth dilution method1,2 or equivalent with standardized inoculum concentrations and standardized concentrations of imipenem powder. The MIC values should be interpreted according to criteria provided in Table 1.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure requires the use of standardized inoculum concentrations2,3. This procedure uses paper disks impregnated with 10-μg imipenem to test the susceptibility of microorganisms to imipenem. The disk diffusion interpretive criteria should be interpreted according to criteria provided in Table 1.

Anaerobic Techniques

For anaerobic bacteria, the susceptibility to imipenem as MICs can be determined by standardized test methods.2,4 The MIC values obtained should be interpreted according to criteria provided in Table 1.

The MIC and disk diffusion values obtained should be interpreted according to the following criteria:

Table 1: Susceptibility Interpretive Criteria for Imipenem

Pathogen Minimum Inhibitory Concentrations MIC (Mμ/mL) Disk Diffusion Zone Diameter (mm)
S I R S I R
Enterobacteriaceae ≤ 1.0 2.0 ≥ 4.0 ≥ 23 20-22 ≤ 19
Pseudomonas aeruginosa ≤ 2 4 ≥ 8 ≥ 19 16-18 ≤ 15
Acinetobacter spp. ≤ 4 8 ≥ 16 ≥ 16 14-15 ≤ 13
Staphylococcus spp.* ≤ 4 8 ≥ 16 ≥ 16 14-15 ≤ 13
Haemophilus influenzae and H. parainfluenzae† ≤ 4 - - ≥ 16 - -
Streptococcus pneumoniae ≤ 0.12 0.25-0.5 ≥ 1 - - -
Anaerobes ≤ 4.0 8.0 ≥ 16.0 - - -
* For oxacillin-susceptible S. aureus and coagulase negative staphylococci results for carbapenems, including imipenem, if tested, should be reported according to the results generated using routine interpretive criteria. For oxacillin-resistant S. aureus and coagulase negative staphylococci, other beta lactam agents, including carbapenems, may appear active in vitro but are not effective clinically. Results for beta lactam agents other than cephalosporins with anti-MRSA activity should be reported as resistant or should not be reported.
† For some organism/antimicrobial combinations, the absence or rare occurrence of resistant strains precludes defining any results categories other than “susceptible”. For strains yielding results suggestive of a “non-susceptible” category, organism identification and antimicrobial susceptibility test results should be confirmed.
‡ For non-meningitis S. pneumoniae isolates, penicillin MICs ≤ 0.06 μg/mL (or oxacillin zones ≥ 20 mm) indicate susceptibility to imipenem.

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound at the infection site reaches the concentrations usually achievable. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound at the infection site reaches the concentrations usually achievable, and that other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory control microorganisms to ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test. Quality control microorganisms are specific strains of organisms with intrinsic biological properties. QC strains are very stable strains which will give a standard and repeatable susceptibility pattern. The specific strains used for microbiological quality control are not clinically significant. Standard imipenem powder should provide the following range of values noted in Table 2.2

Table 2: Acceptable Quality Control Ranges for Imipenem

Microorganism Minimum Inhibitory Concentrations MIC Range (μg/mL) Disk Diffusion Zone Diameter (mm)
Pseudomonas aeruginosa ATCC 27853 1-4 20-28
Escherichia coli ATCC 25922 0.06-0.25 26-32
Haemophilus influenzae ATCC 49247 - 21-29
Haemophilus influenzae ATCC 49766 0.25-1.0 -
Staphylococcus aureus ATCC 29213 0.015-0.06 -
Enterococcus faecalis ATCC 29212 0.5-2.0 -
Streptococcus pneumoniae ATCC 49619 0.03-0.12 -
Bacteroides fragilis ATCC 25285 0.03-0.25* 0.03-0.125† -
Bacteroides thetaiotaomicron ATCC 29741 0.25-1.0* 0.125-0.5† -
Eubacterium lentum ATCC 43055 0.25-2.0* 0.125-0.5† -
* Quality control ranges for broth microdilution testing
† Quality control ranges for agar dilution testing

REFERENCES

1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard -9th ed. CLSI document M07-A9. CLSI, 950 West Valley Rd., Suite 2500, Wayne, PA 19087, 2012.

2. CLSI. Performance Standards for Antimicrobial Susceptibility Testing; 22nd Informational Supplement. CLSI document M100S22, 2012.

3. CLSI. Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard – 11th ed. CLSI document M02-A11, 2012.

4.CLSI. Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard – 8th ed. CLSI document M11-A8, 2012.

What should i avoid while using imipenem and cilastatin (primaxin im, primaxin iv)?

Antibiotic medicines can cause diarrhea, which may be a sign of a new infection. If you have diarrhea that is watery or has blood in it, call your doctor. Do not use anti-diarrhea medicine unless your doctor tells you to.

Where can i get more information?

Your doctor or pharmacist can provide more information about imipenem and cilastatin.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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