Imipenem/Cilastatin Kabi is indicated for the treatment of the following infections in
adults and children 1 year of age and above (see section 4.4 and 5.1):

• complicated intra-abdominal infections
• severe pneumonia including hospital and ventilator-associated pneumonia
• intra- and post-partum infections
• complicated urinary tract infections
• complicated skin and soft-tissue infections.

Imipenem/Cilastatin Kabi may be used in the management of neutropenic patients with
fever that is suspected to be due to a bacterial infection.
Treatment of patients with bacteraemia that occurs in association with, or is suspected
to be associated with, any of the infections listed above.
Consideration should be given to official guidance on the appropriate use of
antibacterial agents.
 

Posology
The dose recommendations for Imipenem/Cilastatin Kabi represent the quantity of
imipenem/cilastatin to be administered.
The daily dose of Imipenem/Cilastatin Kabi should be based on the type of infection
and given in equally divided doses based on consideration of degree of susceptibility
of the pathogen(s) and the patient's renal function (see also section 4.4 and 5.1).
Adults and adolescents
For patients with normal renal function (creatinine clearance of >90 ml/min), the
recommended dose regimens are:
500 mg/500 mg every 6 hours OR
1000 mg/1000 mg every 8 hours OR every 6 hours
It is recommended that infections suspected or proven to be due to less susceptible
bacterial species (such as Pseudomonas aeruginosa) and very severe infections (e.g. in
neutropenic patients with a fever) should be treated with 1000 mg/1000 mg
administered every 6 hours.
A reduction in dose is necessary when:
creatinine clearance is ≤ 90 ml/min/(see Table 1)
The maximum total daily dose should not exceed 4000 mg/4000 mg per day.
Patients with renal impairment
To determine the reduced dose for adults with impaired renal function:
1. The total daily dose (i.e. 2000/2000, 3000/3000 or 4000/4000 mg) that would
usually be applicable to patients with normal renal function should be selected.
2. From table 1 the appropriate reduced dose regimen is selected according to the
patient's creatinine clearance. For infusion times see Method of administration.

Table 1:

reduced dosage (mg) for patients with renal impairment:

Patients with a creatinine clearance of <15 ml/min
These patients should not receive Imipenem/Cilastatin Kabi unless haemodialysis is
instituted within 48 hours.
Patients on haemodialysis
When treating patients with creatinine clearances of <15 ml/min who are undergoing
dialysis use the dose recommendation for patients with creatinine clearances of 15 to
29 ml/min (see table 1).
Both imipenem and cilastatin are cleared from the circulation during haemodialysis.
The patient should receive Imipenem/Cilastatin Kabi after haemodialysis and at 12
hour intervals timed from the end of that haemodialysis session. Dialysis patients,
especially those with background central nervous system (CNS) disease, should be
carefully monitored; for patients on haemodialysis, Imipenem/Cilastatin Kabi is
recommended only when the benefit outweighs the potential risk of seizures (see
section 4.4).
Currently there are inadequate data to recommend use of Imipenem/Cilastatin Kabi for
patients on peritoneal dialysis.
Patients with hepatic impairment
No dose adjustment is recommended in patients with impaired hepatic function (see
section 5.2).
Elderly people
No dose adjustment is required for older people with normal renal function (see
section 5.2).
Paediatric population ≥1 year of age
For paediatric patients ≥1 year of age, the recommended dose is 15/15 or 25/25
mg/kg/dose administered every 6 hours.
It is recommended that infections suspected or proven to be due to less susceptible
bacterial species (such as Pseudomonas aeruginosa) and very severe infections (e.g.

in neutropenic patients with a fever) should be treated with 25/25 mg/kg administered
every 6 hours.
Paediatric population <1 year of age
Clinical data are insufficient to recommend dosing for children less than 1 year of age
Paediatric population with renal impairment
Clinical data are insufficient to recommend dosing for paediatric patients with renal
impairment (serum creatinine > 2 mg/dl). See section 4.4.
Method of administration
Imipenem/Cilastatin Kabi is to be reconstituted and further diluted (see section 6.2, 6.3
and 6.6) prior to administration. Each dose of ≤ 500 mg/500 mg should be given by
intravenous infusion over 20 to 30 minutes. Each dose >500 mg/500 mg should be
infused over 40 to 60 minutes. In patients who develop nausea during the infusion, the
rate of infusion may be slowed.
For instructions on reconstitution of the medicinal product before administration, see section
6.6.

The  selection  of  imipenem/cilastatin  to  treat  an  individual  patient  should  take  into account the appropriateness of using a carbapenem antibacterial agent based on factors such  as  severity  of  the  infection,  the  prevalence  of  resistance  to  other  suitable antibacterial agents and the risk of selecting for carbapenem-resistant bacteria.Hypersensitivity Serious  and  occasionally  fatal  hypersensitivity  (anaphylactic)  reactions  have  been reported  in  patients  receiving  therapy  with  beta-lactams.  These  reactions  are  more likely to occur in individuals with a history of sensitivity to multiple allergens. Before initiating  therapy  with  Imipenem/Cilastatin  Kabi,  careful  inquiry  should  be  made concerning  previous  hypersensitivity  reactions  to  carbapenems,  penicillins, cephalosporins, other beta-lactams and other allergens (see section 4.3). If an allergic reaction  to  Imipenem/Cilastatin  Kabi  occurs,  discontinue  the  therapy  immediately. Serious anaphylactic reactions require immediate emergency treatment.Hepatic   Hepatic  function  should  be  closely  monitored  during  treatment  with imipenem/cilastatin  due  to  the  risk  of  hepatic  toxicity  (such  as  increase  in transaminases, hepatic failure and fulminant hepatitis).

Use  in  patients  with  liver  disease:  patients  with  pre-existing  liver  disorders  should have liver function monitored during treatment with imipenem/cilastatin. There is no dose adjustment necessary (see section 4.2).

Haematology A positive direct or indirect Coombs test may develop during treatment with imipenem/cilastatin.

Antibacterial spectrum The  antibacterial  spectrum  of  imipenem/cilastatin  should  be  taken  into  account especially  in  life-threatening  conditions  before  embarking  on  any  empiric  treatment. Furthermore,  due  to  the  limited  susceptibility  of  specific  pathogens  associated  with e.g. bacterial skin and soft-tissue infections, to imipenem/cilastatin, caution should be exercised. The use of imipenem/cilastatin is not suitable for treatment of these types of infections unless the pathogen is already documented and known to be susceptible or there is  a very high suspicion that the most likely pathogen(s) would be suitable for treatment.  Concomitant  use  of  an  appropriate  anti-MRSA  agent  may  be  indicated when  MRSA  infections  are  suspected  or  proven  to  be  involved  in  the  approved indications.  Concomitant  use  of  an  aminoglycoside  may  be  indicated  when Pseudomonas  aeruginosa  infections  are  suspected  or  proven  to  be  involved  in  the approved indications (see section 4.1).

Interaction with valproic acid The concomitant use of imipenem/cilastatin and valproic acid/sodium valproate is not recommended (see section 4.5).

Clostridium difficile Antibiotic-associated  colitis  and pseudomembranous  colitis have been  reported  with imipenem/  cilastatin  and  with  nearly  all  other  anti-bacterial  agents  and  may  range from mild to life-threatening in severity. It is important to consider this diagnosis in patients  who  develop  diarrhoea  during  or  after  the  use  of  imipenem/cilastatin  (see section  4.8).  Discontinuation  of  therapy  with  imipenem/cilastatin  and  the administration  of  specific  treatment  for  Clostridium  difficile  should  be  considered. Medicinal products that inhibit peristalsis should not be given.

Meningitis   Imipenem/Cilastatin Kabi is not recommended for the therapy of meningitis.

Renal impairment Imipenem-cilastatin  accumulates  in  patients  with  reduced  kidney  function.  CNS adverse  reactions  may  occur  if  the  dose  is  not  adjusted  to  the  renal  function,  see section 4.2 and 4.4 “Central nervous system” in this section.

Central nervous system:

CNS adverse reactions such as myoclonic activity, confusional states, or seizures have been reported, especially when recommended doses based on renal function and body weight  were  exceeded.  These  experiences  have  been  reported  most  commonly  in patients  with  CNS  disorders  (e.g.  brain  lesions  or  history  of  seizures)  and/or compromised renal function in whom accumulation of the administered entities could occur. Hence close adherence to recommended dose schedules is urged especially in these patients (see section 4.2). Anticonvulsant therapy should be continued in patients with a known seizure disorder.

Special  awareness  should  be  made  to  neurological  symptoms  or  convulsions  in children  with  known  risk  factors  for  seizures,  or  on  concomitant  treatment  with medicinal products lowering the seizures threshold.

If focal tremors, myoclonus or seizures occur, patient should be evaluated
neurologically and placed on anticonvulsant therapy if not already instituted. If CNS
symptoms continue, the dose of Imipenem/Cilastatin Kabi should be decreased or
discontinued.
Patients with creatinine clearances of <15 ml/min should not receive
Imipenem/Cilastatin Kabi unless haemodialysis is instituted within 48 hours. For
patients on haemodialysis, Imipenem/Cilastain Kabi is recommended only when the
benefit outweighs the potential risk of seizures (see section 4.2)
Paediatric population
Clinical data are insufficient to recommend the use of Imipenem/Cilastatin Kabi in
children under 1 year of age or paediatric patients with impaired renal function (serum
creatinine >2 mg/dl). See also above under Central nervous system.
sodium per vial/bottle which should be taken into consideration by patients on a
controlled sodium diet.
 

Generalized seizures have been reported in patients who received ganciclovir and
imipenem/cilastatin. These medicinal products should not be used concomitantly
unless the potential benefit outweighs the risks.
Decreases in valproic acid levels that may fall below the therapeutic range have been
reported when valproic acid was co-administered with carbapenem agents. The
lowered valproic acid levels can lead to inadequate seizure control; therefore,
concomitant use of imipenem and valproic acid/sodium valproate is not recommended
and alternative antibacterial or anti-convulsant therapies should be considered (see
section 4.4).
Oral anti-coagulants
Simultaneous administration of antibiotics with warfarin may augment its anti-
coagulant effects.

There have been many reports of increases in the anti-coagulant effects of orally
administered anti-coagulant agents, including warfarin in patients who are
concomitantly receiving antibacterial agents. The risk may vary with the underlying
infection, age and general status of the patient so that the contribution of the antibiotic
to the increase in INR (international normalised ratio) is difficult to assess. It is
recommended that the INR should be monitored frequently during and shortly after coadministration
of antibiotics with an oral anti-coagulant agent.
Concomitant administration of imipenem/cilastatin and probenecid resulted in minimal
increases in the plasma levels and plasma half-life of imipenem. The urinary recovery
of active (non-metabolized) imipenem decreased to approximately 60% of the dose
when imipenem/cilastatin was administered with probenecid. Concomitant
administration of imipenem/cilastatin and probenecid doubled the plasma level and
half-life of cilastatin, but had no effect on urine recovery of cilastatin.
Paediatric population
Interaction studies have only been performed in adults.
 

Pregnancy
There are no adequate and well-controlled studies for the use of imipenem/ cilastatin
in pregnant women.
Studies in pregnant monkeys have shown reproductive toxicity (see section 5.3). The
potential risk for humans is unknown.
Imipenem/Cilastatin Kabi should be used during pregnancy only if the potential
benefit justifies the potential risk to the foetus
Breast-feeding
Imipenem and cilastatin are excreted into the mother’s milk in small quantities. Little
absorption of either compound occurs following oral administration. Therefore it is
unlikely that the suckling infant will be exposed to significant quantities. If the use of
Imipenem/Cilastatin Kabi is deemed necessary, the benefit of breast feeding for the
child should be weighed against the possible risk for the child.
Fertility
There are no data available regarding potential effects of imipenem/cilastatin
treatment on male or female fertility.
 

No studies on the effects on the ability to drive and use machines have been
performed. However, there are some side effects (such as hallucination, dizziness,
somnolence, and vertigo) associated with this product that may affect some patients’
ability to drive or operate machinery (see section 4.8).
 

In clinical trials including 1,723 patients treated with imipenem/cilastatin intravenous
the most frequently reported systemic adverse reactions that were reported at least
possibly related to therapy were nausea (2.0%), diarrhoea (1.8%), vomiting (1.5%),
rash (0.9%), fever (0.5%), hypotension (0.4%), seizures (0.4%) (see section 4.4),
dizziness (0.3%), pruritus (0.3%), urticaria (0.2%), somnolence (0.2%). Similarly, the
most frequently reported local adverse reactions were phlebitis/thrombophlebitis
(3.1%), pain at the injection site (0.7%), erythema at the injection site (0.4%) and vein
induration (0.2%). Increases in serum transaminases and in alkaline phosphatase are
also commonly reported.
The following adverse reactions have been reported in clinical studies or during postmarketing
experience.
All adverse reactions are listed under system organ class and frequency: Very
common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare
(≥1/10,000 to <1/1,000), Very rare (<1/10,000) and not known (cannot be estimated
from the available data).
Within each frequency grouping, undesirable effects are presented in order of
decreasing seriousness.
System Organ Class Frequency Event
Infections and infestations Rare pseudomembranous colitis, candidiasis
Very rare gastro-enteritis
Blood and lymphatic system
disorders
Common eosinophilia
Uncommon pancytopenia, neutropenia, leucopenia,
thrombocytopenia, thrombocytosis
Rare agranulocytosis
Very rare haemolytic anaemia, bone marrow
depression
Immune system disorders Rare anaphylactic reactions
Psychiatric disorders Uncommon psychic disturbances including
hallucinations and confusional states
Nervous system disorders Uncommon seizures, myoclonic activity, dizziness,
somnolence
Rare encephalopathy, paraesthesia, focal
tremor, taste perversion
Very rare aggravation of myasthenia gravis,
headache
Not known agitation, dyskinesia
Ear and labyrinth disorders Rare hearing loss
Very rare vertigo, tinnitus
Cardiac disorders Very rare cyanosis, tachycardia, palpitations
Vascular disorders Common thrombophlebitis
Uncommon hypotension
Very rare flushing
Respiratory, thoracic and Very rare dyspnoea, hyperventilation,

mediastinal disorders pharyngeal pain
Gastrointestinal disorders Common diarrhoea, vomiting, nausea
Medicinal product-related nausea
and/or vomiting appear to occur more
frequently in granulocytopenic patients
than in non-granulocytopenic patients
treated with imipenem/cilastatin
Rare staining of teeth and/or tongue
Very rare haemorrhagic colitis, abdominal pain,
heartburn, glossitis, tongue papilla
hypertrophy, increased salivation
Hepatobiliary disorders Rare hepatic failure, hepatitis
Very rare fulminant hepatitis
Skin and subcutaneous
tissue disorders
Musculoskeletal and
connective tissue disorders
Common rash (e.g. exanthematous)
Uncommon urticaria, pruritus
Rare toxic epidermal necrolysis,
angioedema, Stevens-Johnson
syndrome, erythema multiforme,
exfoliative dermatitis
Very rare hyperhidrosis, skin texture changes
Very rare polyarthralgia, thoracic spine pain
Renal and urinary disorders Rare acute renal failure, oligurial/anuria,
polyuria, urine discoloration (harmless
and should not be confused with
haematuria)
The role of imipenem/cilastatin in
changes in renal function is difficult to
assess, since factors predisposing to prerenal
azotemia or to impaired renal
function usually have been present.
Reproductive system and Very rare pruritus vulvae
breast disorders
General disorders and Uncommmon fever, local pain and induration at the
administration site injection site, erythema at the injection
conditions site
Very rare chest discomfort, asthenia/weakness
Investigations Common increases in serum transaminases,
increases in serum alkaline
phosphatase
Uncommon a positive direct Coombs' test,
prolonged prothrombin time,
decreased haemoglobin, increases in
serum bilirubin, elevations in serum
creatinine, elevations in blood urea
nitrogen
Paediatric population (≥3 months of age)

In studies of 178 paediatric patients ≥3 months of age, the reported adverse reactions were
consistent with those reported for adults.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows
continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are
asked to report any suspected adverse reactions via the national reporting system listed below:
 

Symptoms of overdose that can occur are consistent with the adverse reaction profile;
these may include seizures, confusion, tremors, nausea, vomiting, hypotension,
bradycardia. No specific information is available on treatment of overdose with
Imipenem/Cilastatin Kabi. Imipenem - cilastatin sodium are haemodialysable.
However, usefulness of this procedure in the overdosage setting is unknown

Pharmacotherapeutic group: Antibacterials for systemic use, carbapenems.ATC code:
J01D H51
Mechanism of action Mode of action
Imipenem/Cilastatin Kabi consists of two components: imipenem and cilastatin
sodium in a 1:1 ratio by weight.
Imipenem, also referred to as N-formimidoyl-thienamycin, is a semi-synthetic
derivative of thienamycin, the parent compound produced by the filamentous
bacterium Streptomyces cattleya.
Imipenem exerts its bactericidal activity by inhibiting bacterial cell wall synthesis in
Gram-positive and Gram-negative bacteria through binding to penicillin-binding
proteins (PBPs).
Cilastatin sodium is a competitive, reversible and specific inhibitor of
dehydropeptidase-I, the renal enzyme which metabolizes and inactivates imipenem. It
is devoid of intrinsic antibacterial activity and does not affect the antibacterial activity
of imipenem.
Pharmacokinetic/Pharmacodynamic (PK/PD) relationship
Similar to other beta-lactam antibacterial agents, the time that imipenem
concentrations exceed the MIC (T>MIC) has been shown to best correlate with
efficacy.
Mechanism/s of Resistance
Resistance to imipenem may be due to the following:
10(17)
Decreased permeability of the outer membrane of Gram-negative bacteria (due to
diminished production of porins)
Imipenem may be actively removed from the cell with an efflux pump.
Reduced affinity of PBPs to imipenem
Imipenem is stable to hydrolysis by most beta-lactamases, including penicillinases and
cephalosporinases produced by gram-positive and gram-negative bacteria, with the
exception of relatively rare carbapenem hydrolysing beta-lactamases. Species resistant
to other carbapenems do generally express co-resistance to imipenem. There is no
target-based cross-resistance between imipenem and agents of the quinolone,
aminoglycoside, macrolide and tetracycline classes.
Breakpoints
EUCAST MIC breakpoints for imipenem to separate susceptible (S) pathogens from resistant
(R) pathogens are as follows (v 1,1 2010-04-27):
Enterobacteriaceae
1
: S ≤ 2 mg/l, R >8 mg/l
Pseudomonas spp.
2
: S ≤4 mg/l, R >8 mg/l
Acinetobacter spp.: S ≤2 mg/l, R >8 mg/l
Staphylococcus spp.
3
: Inferred from cefoxitin susceptibility
Enterococcus spp.: S ≤4 mg/l, R >8 mg/l
Streptococcus A, B, C, G: The beta-lactam susceptibility of beta-haemolytic
streptococcus groups A, B, C and G is inferred from the penicillin susceptibility.
Streptococcus pneumoniae
4
: S ≤2 mg/l, R >2 mg/l
Other streptococci
4
: S ≤2 mg/l, R >2 mg/l
Haemophilus influenzae
4
: S ≤2 mg/l, R >2 mg/l
Moraxalla catarrhalis
4
: S ≤2 mg/l, R >2 mg/l
Neisseria gonorrhoeae: There is insufficient evidence that Neisseria gonorrhoeae is a
good target for therapy with imipenem.
Gram-positive anaerobes: S ≤2 mg/l, R >8 mg/l
Gram-negative anaerobes: S ≤2 mg/l, R >8 mg/l
Non-species related breakpoints
5
: S ≤2 mg/l, R >8 mg/l
1Proteus and Morganella species are considered poor targets for imipenem.
2The breakpoints for Pseudomonas relate to high dose frequent therapy (1g every 6 hours).
3Susceptibility of staphylococci to carbapenems is inferred from the cefoxitin susceptibility.
4Strains with MIC values above the susceptible breakpoint are very rare or not yet reported.
The identification and antimicrobial susceptibility tests on any such isolate must be repeated
and if the result is confirmed the isolate must be sent to a reference laboratory. Until there is
evidence regarding clinical response for confirmed isolates with MIC above the current
resistant breakpoint they should be reported resistant.
5Non- species related breakpoint have been determined mainly on the basis of PK/PD data and
are independent of MIC distributions of specific species. They are for use only for species not
mentioned in the overview of species-related breakpoints or footnotes.
Susceptibility
The prevalence of acquired resistance may vary geographically and with time for
selected species and local information on resistance is desirable, particularly when
treating severe infections. As necessary, expert advice should be sought when the local
prevalence of resistance is such that the utility of the agent in at least some types of
infections is questionable.
Commonly susceptible species:
11(17)
Gram-positive aerobes:
Enterococcus faecalis
*
Staphylococcus aureus (Methicillin-susceptible)
Staphylococcus coagulase negative (Methicillin-susceptible)
Streptococcus agalactiae
Streptococcus pneumoniae
Streptococcus pyogenes
Streptococcus viridans group
Gram-negative aerobes:
Citrobacter freundii
Enterobacter aerogenes
Enterobacter cloacae
Escherichia coli
Haemophilus influenzae
Klebsiella oxytoca
Klebsiella pneumoniae
Moraxella catarrhalis
Serratia marcescens
Gram-positive anaerobes:
**
Clostridium perfringens
**
Peptostreptococcus spp.
Gram-negative anaerobes:
Bacteroides fragilis
Bacteroides fragilis group
Fusobacterium spp.
Porphyromonas asaccharolytica
Prevotella spp.
Veillonella spp.
Species for which acquired resistance may be a problem:
Gram-negative aerobes:
Acinetobacter baumannii
Pseudomonas aeruginosa
Inherently resistant species:
Gram positive aerobes:
Enterococcus faecium
Gram negative aerobes:
Some strains of Burkholderia cepacia (formerly Pseudomonas cepacia)
Legionella spp.
Stenotrophomonas maltophilia (formerly Xanthomonas maltophilia, formerly
Pseudomonas maltophilia)
Others:
Chlamydia spp.
Chlamydophila spp.
Mycoplasma spp.
Ureoplasma urealyticum
All methicillin-resistant staphylococci are resistant to imipenem/cilastatin.
**
EUCAST non-species related breakpoint is used.
 

Imipenem
AbsorptionIn normal volunteers, intravenous infusion of imipenem/cilastatin over 20
minutes resulted in peak plasma levels of imipenem ranging from 12 to 20 jig/ml for
the 250 mg/250 mg dose, from 21 to 58 jig/ml for the 500 mg/500 mg dose, and from
41 to 83 jig/ml for the 1000 mg/1000 mg dose. The mean peak plasma levels of
imipenem following the 250 mg/250 mg, 500 mg/500 mg, and 1000 mg /1000 mg
doses were 17, 39, and 66 jig/ml, respectively. At these doses, plasma levels of
imipenem decline to below 1 jig/ml or less in four to six hours.
Distribution
The binding of imipenem to human serum proteins is approximately 20%.
Biotransformation
When administered alone, imipenem is metabolized in the kidneys by
dehydropeptidase-I. Individual urinary recoveries ranged from 5 to 40%, with an
average recovery of 15-20% in several studies.
Cilastatin is a specific inhibitor of dehydropeptidase-I enzyme and effectively inhibits
metabolism of imipenem so that concomitant administration of imipenem and
cilastatin allows therapeutic antibacterial levels of imipenem to be attained in both
urine and plasma.
Elimination
The plasma half-life of imipenem was one hour. Approximately 70% of the
administered antibiotic was recovered intact in the urine within ten hours, and no
further urinary excretion of imipenem was detectable. Urine concentrations of
imipenem exceeded 10 jig/ml for up to eight hours after a 500 mg/500 mg dose of
imipenem/cilastatin. The remainder of the administered dose was recovered in the
urine as antibacterially inactive metabolites, and faecal elimination of imipenem was
essentially nil.
No accumulation of imipenem in plasma or urine has been observed with regimens of
imipenem/cilastatin, administered as frequently as every six hours, in patients with
normal renal function.
Cilastatin
Absorption
Peak plasma levels of cilastatin, following a 20 minute intravenous infusion of
imipenem/cilastatin, ranged from 21 to 26 jig/ml for the 250 mg/250 mg dose, from 21
to 55 jig/ml for the 500 mg/500 mg dose and from 56 to 88 jig/ml for the 1000
mg/1000 mg dose. The mean peak plasma levels of cilastatin following the 250
mg/250 mg, 500 mg/500 mg, and 1000 mg/1000 mg doses were 22, 42, and 72 jig/ml
respectively.
Distribution

The binding of cilastatin to human serum proteins is approximately 40%.
Biotransformation and elimination
The plasma half-life of cilastatin is approximately one hour. Approximately 70-80% of
the dose of cilastatin was recovered unchanged in the urine as cilastatin within 10
hours of administration of imipenem/cilastatin. No further cilastatin appeared in the
urine thereafter. Approximately 10% was found as the N-acetyl metabolite, which has
inhibitory activity against dehydropeptidase comparable to that of cilastatin. Activity
of dehydropeptidase-I in the kidney returned to normal levels shortly after the
elimination of cilastatin from the blood stream.
Pharmacokinetics in special populations
Renal insufficiency
Following a single 250 mg/250 mg intravenous dose of imipenem/cilastatin, the area
under the curve (AUCs) for imipenem increased 1.1-fold, 1.9-fold, and 2.7-fold in
2
subjects with mild (Creatinine Clearance (CrCL) 50-80 ml/min/1.73 m ), moderate
2 2
(CrCL 30-<50 ml/min/1.73 m ), and severe (CrCL <30 ml/min/1.73 m) renal
impairment, respectively, compared to subjects with normal renal function (CrCL >80
2
ml/min/1.73 m ), and AUCs for cilastatin increased 1.6-fold, 2.0-fold, and 6.2-fold in
subjects with mild, moderate, and severe renal impairment, respectively, compared to
subjects with normal renal function. Following a single 250 mg/250 mg intravenous
dose of imipenem/cilastatin given 24 hours after haemodialysis, AUCs for imipenem
and cilastatin were 3.7-fold and 16.4-fold higher, respectively, as compared to
subjects with normal renal function. Urinary recovery, renal clearance and plasma
clearance of imipenem and cilastatin decrease with decreasing renal function
following intravenous administration of imipenem/cilastatin. Dose adjustment is
necessary for patients with impaired renal function (see section 4.2).
Hepatic insufficiency
The pharmacokinetics of imipenem in patients with hepatic insufficiency have not
been established. Due to the limited extent of hepatic metabolism of imipenem, its
pharmacokinetics are not expected to be affected by hepatic impairment. Therefore,
no dose adjustment is recommended in patients with hepatic impairment (see section
4.2).
Paediatric population
The average clearance (CL) and volume of distribution (Vdss) for imipenem were
approximately 45% higher in paediatric patients (3 months to 14 years) as compared
to adults. The AUC for imipenem following administration of 15/15 mg/kg per body
weight of imipenem/cilastatin to paediatric patients was approximately 30% higher
than the exposure in adults receiving a 500 mg/500 mg dose. At the higher dose, the
exposure following administration of 25/25 mg/kg imipenem/cilastatin to children
was 9% higher as compared to the exposure in adults receiving a 1000 mg/1000 mg
dose.
Elderly
In healthy older volunteers (65 to 75 years of age with normal renal function for their
age), the pharmacokinetics of a single dose of imipenem/cilastatin 500 mg/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 were 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 was observed (see section 4.2).
 

Non-clinical data reveal no special hazard for humans based on repeated dose toxicity
and genotoxicity studies.
Animal studies showed that the toxicity produced by imipenem, as a single entity, was
limited to the kidney. Co-administration of cilastatin with imipenem in a 1:1 ratio
prevented the nephrotoxic effects of imipenem in rabbits and monkeys. Available
evidence suggests that cilastatin prevents the nephrotoxicity by preventing entry of
imipenem into the tubular cells.
A teratology study in pregnant cynomolgus monkeys given imipenem-cilastatin
sodium at doses of 40/40 mg/kg/day (bolus intravenous injection) resulted in maternal
toxicity including emesis, inappetence, body weight loss, diarrhoea, abortion, and
death in some cases. When doses of imipenem-cilastatin sodium (approximately
100/100 mg/kg/day or approximately 3 times the usual recommended daily human
intravenous dose) 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 (see
section 4.6).
Long term studies in animals have not been performed to evaluate carcinogenic
potential of imipenem-cilastatin.
 

Sodium hydrogen carbonate
 

This medicinal product is chemically incompatible with lactate and should not be reconstituted
in diluents containing lactate. However, it can be administered into an I.V. system through
which a lactate solution is being infused.
This medicinal product must not be mixed with other medicinal products except those
mentioned in section 6.6.
 

Do not store above 25ºC.
For storage conditions after reconstitution of the medicinal product, see section 6.3.
 

Imipenem/Cilastatin Kabi 500 mg/500 mg, powder for solution for infusion
Nature: uncolored glass vial Type III, 20 ml volume closed with bromobutyl rubber
stopper 20mm and covered with aluminum flip-off cap and uncolored glass bottle
Type II, 100 ml volume closed with bromobutyl rubber stopper 32mm and covered
with aluminum flip-off cap
Contents: Each pack contains: 10 x 20 ml vials and 10 x 100 ml bottles
 

Each container is for single use only.
Reconstitution:
Contents of each container must be transferred to 50 mL (for 250mg strength) and 100 mL
(for 500mg strength) of an appropriate infusion solution (see section 6.2 and 6.3): 0.9%
sodium chloride. In exceptional circumstances where 0.9% sodium chloride cannot be used for
clinical reasons 5% glucose may be used instead.
A suggested procedure is to add approximately 10 ml of the appropriate infusion solution to
the container.
Shake well and transfer the resulting mixture to the infusion solution container.
CAUTION: THE MIXTURE IS NOT FOR DIRECT INFUSION.
Repeat with an additional 10 ml of infusion solution to ensure complete transfer of
container contents to the infusion solution. The resulting mixture should be agitated
until a clear solution is obtained.
16(17)
The concentration of the reconstituted solution following the above procedure is approximately
5 mg/ml for both imipenem and cilastatin.
Variations of colour, from colourless to yellow, do not affect the potency of the product.
Any unused medicinal product or waste material should be disposed of in accordance
with local requirements.