Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2023 Publisher: Merck Sharp & Dohme (UK) Limited, 120 Moorgate, London, EC2M 6UR, UK
Pharmacotherapeutic group: Antibacterials for systemic use, carbapenems
ATC code: J01DH51
PRIMAXIN 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.
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.
Resistance to imipenem may be due to the following:
The EUCAST MIC breakpoints for imipenem are as follows (v 12.0, valid from 01-01-2022):
| Organism Group | Minimum Inhibitory Concentrations (mg/L) | |
|---|---|---|
| Susceptible ≤ | Resistant > | |
| Enterobacterales | 2 | 4 |
| Enterobacterales1 (Morganella morganii, Proteus spp. and Providencia spp.) | 0.001 | 4 |
| Pseudomonas spp. | 0.001 | 4 |
| Acinetobacter spp. | 2 | 4 |
| Staphylococcus spp. | Inferred from cefoxitin susceptibility | |
| Enterococcus spp. | 0.001 | 4 |
| Streptococcus A, B, C, G | Inferred from the benzylpenicillin susceptibility | |
| Streptococcus pneumoniae | 2 | 2 |
| Viridans group streptococci | 2 | 2 |
| Haemophilus influenzae | 2 | 2 |
| Moraxalla catarrhalis2 | 2 | 2 |
| Gram-positive anaerobes except Clostridioides difficile | 2 | 4 |
| Gram-negative anaerobes | 2 | 4 |
| Burkholderia pseudomallei | 2 | 2 |
| Non-species related breakpoints3 | 2 | 4 |
1 The intrinsically low activity of imipenem against Morganella morganii, Proteus spp. and Providencia spp. requires the high exposure of imipenem.
2 Non-susceptible isolates are rare or not yet reported. The identification and antimicrobial susceptibility test result on any such isolate must be confirmed and the isolate sent to a reference laboratory.
3 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.
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.
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
Klebsiella aerogenes (formerly Enterobacter aerogens)
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.
Gram-negative aerobes:
Acinetobacter calcoaceticus baumannii complex
Pseudomonas aeruginosa
Gram positive aerobes:
Enterococcus faecium
Gram negative aerobes:
Some strains of Burkholderia cepacia complex
Legionella spp.
Stenotrophomonas maltophilia (formerly Xanthomonas maltophilia, formerly Pseudomonas maltophilia)
Chlamydia spp.
Chlamydophila spp.
Mycoplasma spp.
Ureoplasma urealyticum
* All methicillin-resistant staphylococci are resistant to imipenem/cilastatin.
** EUCAST non-species related breakpoint is used.
In normal volunteers, intravenous infusion of PRIMAXIN 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.
The binding of imipenem to human serum proteins is approximately 20%.
When administered alone, imipenem is metabolised 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 PRIMAXIN. 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 PRIMAXIN, administered as frequently as every six hours, in patients with normal renal function.
Peak plasma levels of cilastatin, following a 20 minute intravenous infusion of PRIMAXIN, 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.
The binding of cilastatin to human serum proteins is approximately 40%.
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 PRIMAXIN. 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.
Following a single 250 mg/250 mg intravenous dose of PRIMAXIN, the area under the curve (AUCs) for imipenem increased 1.1-fold, 1.9-fold, and 2.7-fold in subjects with mild (Creatinine Clearance (CrCL) 50-80 ml/min/1.73 m²), moderate (CrCL 30-<50 ml/min/1.73 m²), and severe (CrCL <30 ml/min/1.73 m²) renal impairment, respectively, compared to subjects with normal renal function (CrCL >80 ml/min/1.73 m²), 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 PRIMAXIN 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 PRIMAXIN. Dose adjustment is necessary for patients with impaired renal function (see section 4.2).
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).
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.
In healthy elderly volunteers (65 to 75 years of age with normal renal function for their age), the pharmacokinetics of a single dose of PRIMAXIN 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).
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, 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.
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