Skip to Content

CIATENEM 500MG/500MG POWDER FOR SOLUTION FOR INFUSION

Active substance(s): CILASTATIN SODIUM / IMIPENEM MONOHYDRATE

View full screen / Print PDF » Download PDF ⇩
Transcript
SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Ciatenem 500mg/500mg Powder for Solution for Infusion

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 500 mg imipenem (as 530 mg imipenem monohydrate) and 500 mg
cilastatin (as 530 mg cilastatin sodium salt).
Excipient with known effect:
Ciatenem 500mg/500mg powder for solution for infusion contains 20 mg sodium hydrogen
carbonate.

3

PHARMACEUTICAL FORM
Powder for solution for infusion.
White to almost white or light (pale) yellow powder.

4.

CLINICAL PARTICULARS

4.1.

Therapeutic indications
Ciatenem 500mg/500mg Powder for Solution for Infusion is indicated for the
treatment of the following infections in adults and children 1 year of age and above
(see sections 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
Ciatenem 500mg/500mg Powder for Solution for Infusion 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.

4.2

Posology and method of administration

Posology
The dose recommendations for Ciatenem 500mg/500mg Powder for Solution for Infusion
represent the quantity of imipenem/cilastatin to be administered.
The daily dose of Ciatenem 500mg/500mg Powder for Solution for Infusion should be based
on the type and severity of infection, the pathogen(s) isolated, the patient's renal function and
body weight (see also section 4.4 and 5.1).
Adults and adolescents
2

For patients with normal renal function (creatinine clearance of >70 ml/min/1.73 m ), 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:
2
- creatinine clearance is ≤ 70 ml/min/l.73 m (see Table 1) or
- body weight is < 70 kg. The proportionate dose for patients < 70 kg would be calculated
using the following formula:
Actual body weight (kg) X standard dose
70 (kg)
The maximum total daily dose should not exceed 4000 mg/4000 mg per day.
Adults with impaired renal function
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 dose in adults with impaired renal function and body weight ≥70 kg*
Total daily dose for patients with
normal renal function (mg/day)

2

Creatinine clearance (ml/min/1.73 m )
41-70
21-40
6-20
dose in mg (interval hrs)
2000/2000
500/500 (8)
250/250 (6)
250/250 (12)
3000/3000
500/500 (6)
500/500 (8)
500/500 (12)**
4000/4000
750/750 (8)
500/500 (6)
500/500 (12)**
*A further proportionate reduction in dose administered must be made for patients with a
body weight

<70 kg. The proportionate dose for patients <70 kg would be calculated by dividing the
patient's actual body weight (in kg) by 70 kg multiplied by the respective dose recommended
in Table 1.
**When the 500 mg/500 mg dose is used in patients with creatinine clearances of 6 to 20
2

ml/min/l.73 m , there may be an increased risk of seizures.
2

Patients with a creatinine clearance of ≤5 ml/min/1.73 m
These patients should not receive Ciatenem 500mg/500mg Powder for Solution for Infusion
unless haemodialysis is instituted within 48 hours.
Patients on haemodialysis
2
When treating patients with creatinine clearances of ≤5 ml/min/1.73 m who are undergoing
dialysis use the dose recommendation for patients with creatinine clearances of 6 to 20
2
ml/min/1.73 m (see table 1).
Both imipenem and cilastatin are cleared from the circulation during haemodialysis. The
patient should receive Ciatenem 500mg/500mg Powder for Solution for Infusion 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, Ciatenem 500mg/500mg
Powder for Solution for Infusion 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 Ciatenem 500mg/500mg Powder for
Solution for Infusion for patients on peritoneal dialysis.
Hepatic impairment
No dose adjustment is recommended in patients with impaired hepatic function (see section
5.2).
Elderly population
No dose adjustment is required for the elderly patients 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
Ciatenem 500mg/500mg Powder for Solution for Infusion 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.

4.3




4.4

Contraindications
Hypersensitivity to the active substances or to any of the excipients listed in
section 6.1.
Hypersensitivity to any other carbapenem antibacterial agent.
Severe hypersensitivity (e.g. anaphylactic reaction, severe skin reaction) to any
other type of betalactam antibacterial agent (e.g. penicillins or cephalosporins).
Special warnings and precautions for use

General
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
Ciatenem 500mg/500mg Powder for Solution for Infusion , 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 Ciatenem
500mg/500mg Powder for Solution for Infusion 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 softtissue 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
Ciatenem 500mg/500mg Powder for Solution for Infusion 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 the
subheading “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, patients should be evaluated neurologically
and placed on anticonvulsant therapy if not already instituted. If CNS symptoms continue, the
dose of Ciatenem 500mg/500mg Powder for Solution for Infusion should be decreased or
discontinued.
2

Patients with creatinine clearances of ≤5 ml/min/1.73 m should not receive Ciatenem
500mg/500mg Powder for Solution for Infusion unless haemodialysis is instituted within 48
hours. For patients on haemodialysis, Ciatenem 500mg/500mg Powder for Solution for
Infusion 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 Ciatenem 500mg/500mg Powder for
Solution for Infusion 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.

Ciatenem 500mg/500mg Powder for Solution for Infusion contains 1.6 mmol (or 37.6 mg)
sodium per dose. To be taken into consideration by patients on a controlled sodium diet

4.5

Interaction with other medicinal products and other forms of interaction
Generalized seizures have been reported in patients who received ganciclovir and
Ciatenem 500mg/500mg Powder for Solution for Infusion. 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 anticoagulant 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
co-administration of antibiotics with an oral anti-coagulant agent.
Concomitant administration of Ciatenem 500mg/500mg Powder for Solution for
Infusion 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 Ciatenem 500mg/500mg
Powder for Solution for Infusion was administered with probenecid. Concomitant
administration of Ciatenem 500mg/500mg Powder for Solution for Infusion and
probenecid doubled the plasma level and half-life of cilastatin, but had no effect on
urine recovery of cilastatin.

4.6

Fertility, pregnancy and lactation

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.
Ciatenem 500mg/500mg Powder for Solution for Infusion 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 Ciatenem
500mg/500mg Powder for Solution for Infusion is deemed necessary, the benefit of breastfeeding 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.

4.7.

Effects on ability to drive and use machines
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).

4.8

Undesirable effects

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
Infections and infestations
Blood and lymphatic system
disorders

Frequency
Rare
Very rare
Common

Event
pseudomembranous colitis, candidiasis
gastro-enteritis
eosinophilia

Uncommon

pancytopenia, neutropenia, leucopenia,
thrombocytopenia, thrombocytosis
agranulocytosis
haemolytic anaemia, bone marrow
depression
anaphylactic reactions
psychic disturbances including

Rare
Very rare
Immune system disorders
Psychiatric disorders

Rare
Uncommon

Nervous system disorders

Uncommon
Rare
Very rare

Ear and labyrinth disorders
Cardiac disorders
Vascular disorders

Respiratory, thoracic and
mediastinal disorders
Gastrointestinal disorders

Rare
Very rare
Very rare
Common
Uncommon
Very rare
Very rare
Common

Rare
Very rare

Hepatobiliary disorders
Skin and subcutaneous tissue
disorders

Rare
Very rare
Common
Uncommon
Rare

Musculoskeletal and
connective tissue disorders
Renal and urinary disorders

Reproductive system and
breast disorders
General disorders and
administration site conditions
Investigations

Very rare
Very rare
Rare

Very rare
Uncommon
Very rare
Common
Uncommon

hallucinations and confusional states
seizures, myoclonic activity, dizziness,
somnolence
encephalopathy, paraesthesia, focal
tremor, taste perversion
aggravation of myasthenia gravis,
headache
hearing loss
vertigo, tinnitus
cyanosis, tachycardia, palpitations
thrombophlebitis
hypotension
flushing
dyspnoea, hyperventilation, pharyngeal
pain
diarrhoea, vomiting, nausea
Medicinal product-related nausea and/or
vomiting appear to occur more frequently
in granulocytopenic patients than in nongranulocytopenic patients treated with
imipenem/cilastatin
staining of teeth and/or tongue
haemorrhagic colitis, abdominal pain,
heartburn, glossitis, tongue papilla
hypertrophy, increased salivation
hepatic failure, hepatitis
fulminant hepatitis
rash (e.g. exanthematous)
urticaria, pruritus
toxic epidermal necrolysis, angioedema,
Stevens-Johnson syndrome, erythema
multiforme, exfoliative dermatitis
hyperhidrosis, skin texture changes
polyarthralgia, thoracic spine pain
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 pre-renal
azotemia or to impaired renal function
usually have been present.
pruritus vulvae
fever, local pain and induration at the
injection site, erythema at the injection site
chest discomfort, asthenia/weakness
increases in serum transaminases,
increases in serum alkaline phosphatase
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 Yellow
Card Scheme; website: www.mhra.gov.uk/yellowcard

4.9.

Overdose
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
Ciatenem 500mg/500mg Powder for Solution for Infusion.
Imipenem/cilastatin sodium is haemodialyzable. However, usefulness of this
procedure in the overdose setting is unknown.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterials for systemic use, carbapenems.
ATC code: J01D H51
Mechanism of action
Ciatenem 500mg/500mg Powder for Solution for Infusion 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 Grampositive 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 of resistance

Resistance to imipenem may be due to the following:
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):
1

- Enterobacteriaceae : S ≤2 mg/l, R >8 mg/l
2
- Pseudomonas spp. : S ≤4 mg/l, R >8 mg/l
- Acinetobacter spp.: S ≤2 mg/l, R >8 mg/l
3
- Staphylococcus spp. : 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.
4
- Streptococcus pneumoniae : S ≤2 mg/l, R >2 mg/l
4

- Other streptococci : S ≤2 mg/l, R >2 mg/l
4

- Haemophilus influenzae : S ≤2 mg/l, R >2 mg/l
4

- Moraxalla catarrhalis : 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
5

- Non-species related breakpoints : S ≤2 mg/l, R >8 mg/l
1
2
3

Proteus and Morganella species are considered poor targets for imipenem.
The breakpoints for Pseudomonas relate to high dose frequent therapy (1g every 6 hours).
Susceptibility of staphylococci to carbapenems is inferred from the cefoxitin susceptibility.

4

Strains 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.
5

Non-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
Gram-positive aerobes:
Enterococcus faecalis
Staphylococcus aureus (Methicillin susceptible)*
Staphylococcus coagulase negative(Methicillin-susceptible)
Streptococcus agalactiae
Streptococcus pneumoniae
Streptococcus pyogenes
Streptococcus viridians group
Gram-negative aerobes:
Citrobacter freundii
Enterobacter aerogenes
Enterobacter cloacae
Eschericia 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:
Acetinobacter 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.

Ureaplasma urealyticum
*All methicillin-resistant staphylococci are resistant to imipenem/cilastatin.
**EUCAST non-species related breakpoint is used.

5.2

Pharmacokinetic properties

Imipenem
Plasma concentrations
In normal volunteers, intravenous infusion of Ciatenem 500mg/500mg Powder for Solution
for Infusion over 20 minutes resulted in peak plasma levels of imipenem ranging from 12 to
20 μg/ml for the 250 mg/250 mg dose, from 21 to 58 μg/ml for the 500 mg/500 mg dose, and
from 41 to 83 μg/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 μg/ml, respectively. At these doses, plasma levels of imipenem decline to
below 1 μg/ml or less in four to six hours.
Distribution
The binding of imipenem to human serum proteins is approximately 20%.
Biotransformation and elimination
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.
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 μg/ml for up to
eight hours after a 500 mg/500 mg dose of Ciatenem 500mg/500mg Powder for Solution for
Infusion. 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
Ciatenem 500mg/500mg Powder for Solution for Infusion , administered as frequently as
every six hours, in patients with normal renal function.

Cilastatin
Plasma concentrations

Peak plasma levels of cilastatin, following a 20 minute intravenous infusion of Ciatenem
500mg/500mg Powder for Solution for Infusion , ranged from 21 to 26 μg/ml for the 250
mg/250 mg dose, from 21 to 55 μg/ml for the 500 mg/500 mg dose and from 56 to 88 μg/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 μg/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 Ciatenem 500mg/500mg Powder for Solution for Infusion . 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.
Renal insufficiency
Following a single 250 mg/250 mg intravenous dose of Ciatenem 500mg/500mg Powder for
Solution for Infusion , the area under the curve (AUCs) for imipenem increased 1.1-fold, 1.92
fold, and 2.7-fold in subjects with mild (Creatinine Clearance (CrCL) 50-80 ml/min/1.73 m ),
2

2

moderate (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 Ciatenem
500mg/500mg Powder for Solution for Infusion 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 Ciatenem 500mg/500mg Powder for Solution for Infusion . 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 patients
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 elderly volunteers (65 to 75 years of age with normal renal function for their age),
the pharmacokinetics of a single dose of Ciatenem 500mg/500mg Powder for Solution for
Infusion 500 mg/500 mg administered intravenously over 20 minutes were consistent with
those expected in subjects with slight renal impairment for which no dose 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).

5.3.

Preclinical safety data
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

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Sodium hydrogen carbonate.

6.2

Incompatibilities
This medicinal product should not be mixed with lactate solution.
This medicinal product must not be mixed with other medicinal products except those
mentioned in section 6.6.

6.3
Shelf life
3 years
After reconstitution:
Diluted solutions should be used immediately. The time interval between the
beginning of reconstitution and the end of intravenous infusion should not exceed two
hours.

6.4.

Special precautions for storage
Vial of dry Ciatenem 500mg/500mg Powder for Solution for Infusion does not
require any special storage conditions
Do not freeze the reconstituted solution.
For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5

Nature and contents of container
Ciatenem 500mg strength is available in uncoloured glass vials type III having a
capacity of 20 ml stoppered with bromobutyl rubber stoppers having a diameter of 20
mm and with flip-off cap.
Pack sizes:
1 x 500 mg vial
10 x 500 mg vial
Not all pack sizes may be marketed.

6.6

Special precautions for disposal and handling

Each vial is for single use only.

Preparation of intravenous solution
Contents of the vials must be dissolved and transferred to an appropriate infusion
solution to reach a final volume of 100 ml.
A suggested procedure is to add approximately 10 ml from the appropriate infusion
solution (see ‘Compatibility and stability’)to the vial. Shake well and transfer the
resulting suspension to the infusion solution container.
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 container. Take to 100.0 with the same infusion
solution. The resulting mixture should be agitated until a clear solution is obtained.
The concentration of the reconstituted solution following the above procedure is
approximately 5 mg/ml for both imipenem and cilastatin.
The reconstituted solution should be expected visually for particulate matter and
discoloration prior to administration. When reconstituted, Ciatenem 500mg/500mg
Powder for Solution for Infusion ranges from colourless to yellow. Variation of colour
within this range does not affect the potency of product.
Compatibility and stability
Reconstituted solutions should be used immediately. . The time interval between the
beginning of reconstitution and the end of intravenous infusion should not exceed two
hours.
Ciatenem 500mg/500mg Powder for Solution for Infusion can be reconstituted in WFI
or Sodium chloride 9 mg/ml (0.9%) solution for infusion.
Do not freeze the reconstituted solution.
Any unused medicinal product or waste material should be disposed of in accordance
with local requirements.

7

MARKETING AUTHORISATION HOLDER
Actavis Group PTC ehf
Reykjavikurvegur 76-78
220 Hafnarfjordur
Iceland

8

MARKETING AUTHORISATION NUMBER(S)
PL 30306/0113

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
11/08/2014

10

DATE OF REVISION OF THE TEXT
17/11/2015

Expand view ⇕

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

Hide