Ronepem

Ronepem is indicated for the treatment of the following infections in adults and children aged 3 months and older :

- Severe pneumonia, including hospital and ventilator-associated pneumonia.

- Broncho-pulmonary infections in cystic fibrosis

- Complicated urinary tract infections

- Complicated intra-abdominal infections

- Intra- and post-partum infections

- Complicated skin and soft tissue infections

- Acute bacterial meningitis

Ronepem 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 tables below provide general recommendations for dosing.

The dose of meropenem administered and the duration of treatment should take into account the type of infection to be treated, including its severity, and the clinical response.

A dose of up to 2 g three times daily in adults and adolescents and a dose of up to 40 mg/kg three times daily in children may be particularly appropriate when treating some types of infections, such as infections due to less susceptible bacterial species (e.g. Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter spp.), or very severe infections.

Additional considerations for dosing are needed when treating patients with renal insufficiency (see further below).

Adults and Adolescents

Meropenem is usually given by intravenous infusion over approximately 15 to 30 minutes.

Alternatively, doses up to 1 g can be given as an intravenous bolus injection over approximately 5 minutes. There are limited safety data available to support the administration of a 2 g dose in adults as an intravenous bolus injection.

Renal impairment

The dose for adults and adolescents should be adjusted when creatinine clearance is less than 51 ml/min, as shown below. There are limited data to support the administration of these dose adjustments for a unit dose of 2 g.

Meropenem is cleared by haemodialysis and haemofiltration. The required dose should be administered after completion of the haemodialysis cycle.

There are no established dose recommendations for patients receiving peritoneal dialysis.

Hepatic impairment

No dose adjustment is necessary in patients with hepatic impairment.

Dose in elderly patients

No dose adjustment is required for the elderly with normal renal function or creatinine clearance values above 50 ml/min.

Paediatric population

Children under 3 months of age

The safety and efficacy of meropenem in children under 3 months of age have not been established and the optimal dose regimen has not been identified. However, limited pharmacokinetic data suggest that 20 mg/kg every 8 hours may be an appropriate regimen.

Children from 3 months to 11 years of age and up to 50 kg body weight

The recommended dose regimens are shown in the table below:

Children over 50 kg body weight

The adult dose should be administered.

There is no experience in children with renal impairment.

Method of administration

Meropenem is usually given by intravenous infusion over approximately 15 to 30 minutes. Alternatively, meropenem doses of up to 20 mg/kg may be given as an intravenous bolus over approximately 5 minutes. There are limited safety data available to support the administration of a 40 mg/kg dose in children as an intravenous bolus injection.

Hypersensitivity to any other carbapenem antibacterial agent.

Severe hypersensitivity (e.g. anaphylactic reaction, severe skin reaction) to any other type of beta-lactam antibacterial agent (e.g. penicillins or cephalosporins).

The selection of meropenem 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.

Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter spp. resistance

Resistance to penems of Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter spp. varies across the European Union. Prescribers are advised to take into account the local prevalence of resistance in these bacteria to penems.

Hypersensitivity reactions

As with all beta-lactam antibiotics, serious and occasionally fatal hypersensitivity reactions have been reported.

Patients who have a history of hypersensitivity to carbapenems, penicillins or other beta-lactam antibiotics may also be hypersensitive to meropenem. Before initiating therapy with meropenem, careful inquiry should be made concerning previous hypersensitivity reactions to beta-lactam antibiotics.

If a severe allergic reaction occurs, the medicinal product should be discontinued and appropriate measures taken.

Antibiotic-associated colitis

Antibiotic-associated colitis and pseudomembranous colitis have been reported with nearly all anti-bacterial agents, including meropenem, and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of meropenem. Discontinuation of therapy with meropenem and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.

Seizures

Seizures have infrequently been reported during treatment with carbapenems, including meropenem.

Hepatic function monitoring

Hepatic function should be closely monitored during treatment with meropenem due to the risk of hepatic toxicity (hepatic dysfunction with cholestasis and cytolysis).

Use in patients with liver disease: patients with pre-existing liver disorders should have liver function monitored during treatment with meropenem. There is no dose adjustment necessary.

Direct antiglobulin test (Coombs test) seroconversion

A positive direct or indirect Coombs test may develop during treatment with meropenem.

Concomitant use with valproic acid/sodium valproate/valpromide

The concomitant use of meropenem and valproic acid/sodium valproate/valpromide is not recommended.

Ronepem contains sodium.

Ronepem 500 mg: This medicinal product contains approximately 2 mEq of sodium per 500 mg dose which should be taken into consideration by patients on a controlled sodium diet.

Ronepem 1 g: This medicinal product contains approximately 4 mEq of sodium per 1 g dose which should be taken into consideration by patients on a controlled sodium diet.

No studies on the effect on the ability to drive and use machines have been performed. However, when driving or operating machines, it should be taken into account that headache, paraesthesia and convulsions have been reported for meropenem.

Summary of the safety profile

In a review of 4,872 patients with 5,026 meropenem treatment exposures, meropenem-related adverse reactions most frequently reported were diarrhoea (2.3%), rash (1.4%), nausea/vomiting (1.4%) and injection site inflammation (1.1%). The most commonly reported meropenem-related laboratory adverse events were thrombocytosis (1.6%) and increased hepatic enzymes (1.5-4.3%).

Tabulated risk of adverse reactions

In the table below all adverse reactions are listed by 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); not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Paediatric population

Ronepem is licensed for children over 3 months of age. There is no evidence of an increased risk of any adverse drug reaction in children based on the limited available data. All reports received were consistent with events observed in the adult population.

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.

Symptomatic treatments should be considered.

In individuals with normal renal function, rapid renal elimination will occur.

Haemodialysis will remove meropenem and its metabolite.

Pharmacotherapeutic group: antibacterials for systemic use, carbapenems

ATC code: J01DH02

Mechanism of action

Meropenem exerts its bactericidal activity by inhibiting bacterial cell wall synthesis in Gram-positive and Gram-negative bacteria through binding to penicillin-binding proteins (PBPs).

Pharmacokinetic/Pharmacodynamic (PK/PD) relationship

Similar to other beta-lactam antibacterial agents, the time that meropenem concentrations exceed the MIC (T>MIC) has been shown to best correlate with efficacy. In preclinical models meropenem demonstrated activity when plasma concentrations exceeded the MIC of the infecting organisms for approximately 40% of the dosing interval. This target has not been established clinically.

Mechanism of resistance

Bacterial resistance to meropenem may result from: (1) decreased permeability of the outer membrane of Gram-negative bacteria (due to diminished production of porins) (2) reduced affinity of the target PBPs (3) increased expression of efflux pump components, and (4) production of beta-lactamases that can hydrolyse carbapenems.

Localised clusters of infections due to carbapenem-resistant bacteria have been reported in the European Union.

There is no target-based cross-resistance between meropenem and agents of the quinolone, aminoglycoside, macrolide and tetracycline classes. However, bacteria may exhibit resistance to more than one class of antibacterial agents when the mechanism involved include impermeability and/or an efflux pump(s).

Breakpoints

European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoints for MIC testing are presented below.

EUCAST clinical MIC breakpoints for meropenem (2013-02-11, v 3.1)

¹ Meropenem breakpoints for Streptococcus pneumoniae and Haemophilus influenzae in meningitis are 0.25 mg/l (Susceptible) and 1 mg/l (Resistant).

² Isolates 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 sent to a reference laboratory. Until there is evidence regarding clinical response for confirmed isolates with MIC values above the current resistant breakpoint they should be reported resistant.

³ Susceptibility of staphylococci to carbapenems is inferred from the cefoxitin susceptibility.

⁴ Breakpoints relate to meningitis only.

⁵ Non-species related breakpoints have been determined using PK/PD data and are independent of MIC distributions of specific species. They are for use only for organisms that do not have specific breakpoints. Non species related breakpoints are based on the following dosages: EUCAST breakpoints apply to meropenem 1000 mg x 3 daily administered intravenously over 30 minutes as the lowest dose. 2 g x 3 daily was taken into consideration for severe infections and in setting the I/R breakpoint.

6 The beta-lactam susceptibility of streptococcus groups A, B, C and G is inferred from the penicillin susceptibility.

-- = Susceptibility testing not recommended as the species is a poor target for therapy with the drug. Isolates may be reported as R without prior testing.

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.

The following table of pathogens listed is derived from clinical experience and therapeutic guidelines.

Commonly susceptible species

Gram-positive aerobes

Enterococcus faecalis^$

Staphylococcus aureus (methicillin-susceptible)^£

Staphylococcus species (methicillin-susceptible) including Staphylococcus epidermidis

Streptococcus agalactiae (Group B)

Streptococcus milleri group (S. anginosus, S. constellatus, and S. intermedius)

Streptococcus pneumoniae

Streptococcus pyogenes (Group A)

Gram-negative aerobes

Citrobacter freundii

Citrobacter koseri

Enterobacter aerogenes

Enterobacter cloacae

Escherichia coli

Haemophilus influenzae

Klebsiella oxytoca

Klebsiella pneumoniae

Morganella morganii

Neisseria meningitides

Proteus mirabilis

Proteus vulgaris

Serratia marcescens

Gram-positive anaerobes

Clostridium perfringens

Peptoniphilus asaccharolyticus

Peptostreptococcus species (including P. micros, P anaerobius, P. magnus)

Gram-negative anaerobes

Bacteroides caccae

Bacteroides fragilis group

Prevotella bivia

Prevotella disiens

Species for which acquired resistance may be a problem

Gram-positive aerobes

Enterococcus faecium^$â€

Gram-negative aerobes

Acinetobacter species

Burkholderia cepacia

Pseudomonas aeruginosa

Inherently resistant organisms

Gram-negative aerobes

Stenotrophomonas maltophilia

Legionella species

Other micro-organisms

Chlamydophila pneumoniae

Chlamydophila psittaci

Coxiella burnetii

Mycoplasma pneumoniae

^$ Species that show natural intermediate susceptibility

^£ All methicillin-resistant staphylococci are resistant to meropenem

^†Resistance rate > 50% in one or more EU countries.

Glanders and melioidosis: Use of meropenem in humans is based on in vitro B.mallei and B. pseudomallei susceptibility data and on limited human data. Treating physicians should refer to national and/or international consensus documents regarding the treatment of glanders and melioidosis.

In healthy subjects the mean plasma half-life is approximately 1 hour; the mean volume of distribution is approximately 0.25 l/kg (11-27 l) and the mean clearance is 287 ml/min at 250 mg falling to 205 ml/min at 2 g. Doses of 500, 1000 and 2000 mg doses infused over 30 minutes give mean Cmax values of approximately 23, 49 and 115 μg/ml respectively, corresponding AUC values were 39.3, 62.3 and 153 μg.h/ml. After infusion over 5 minutes Cmax values are 52 and 112 μg/ml after 500 and 1000 mg doses respectively. When multiple doses are administered 8-hourly to subjects with normal renal function, accumulation of meropenem does not occur.

A study of 12 patients administered meropenem 1000 mg 8 hourly post-surgically for intra-abdominal infections showed a comparable Cmax and half-life to normal subjects but a greater volume of distribution 27 l.

Distribution

The average plasma protein binding of meropenem was approximately 2% and was independent of concentration. After rapid administration (5 minutes or less) the pharmacokinetics are biexponential but this is much less evident after 30 minutes infusion. Meropenem has been shown to penetrate well into several body fluids and tissues: including lung, bronchial secretions, bile, cerebrospinal fluid, gynaecological tissues, skin, fascia, muscle, and peritoneal exudates.

Biotransformation

Meropenem is metabolised by hydrolysis of the beta-lactam ring generating a microbiologically inactive metabolite. In vitro meropenem shows reduced susceptibility to hydrolysis by human dehydropeptidase-I (DHP-I) compared to imipenem and there is no requirement to co-administer a DHP-I inhibitor.

Elimination

Meropenem is primarily excreted unchanged by the kidneys; approximately 70% (50 -75%) of the dose is excreted unchanged within 12 hours. A further 28% is recovered as the microbiologically inactive metabolite. Faecal elimination represents only approximately 2% of the dose. The measured renal clearance and the effect of probenecid show that meropenem undergoes both filtration and tubular secretion.

Renal insufficiency

Renal impairment results in higher plasma AUC and longer half-life for meropenem. There were AUC increases of 2.4 fold in patients with moderate impairment (CrCL 33-74 ml/min), 5 fold in severe impairment (CrCL 4-23 ml/min) and 10 fold in haemodialysis patients (CrCL <2 ml/min) when compared to healthy subjects (CrCL >80 ml/min). The AUC of the microbiologically inactive ring opened metabolite was also considerably increased in patients with renal impairment. Dose adjustment is recommended for patients with moderate and severe renal impairment.

Meropenem is cleared by haemodialysis with clearance during haemodialysis being approximately 4 times higher than in anuric patients.

Hepatic insufficiency

A study in patients with alcoholic cirrhosis shows no effect of liver disease on the pharmacokinetics of meropenem after repeated doses.

Adult patients

Pharmacokinetic studies performed in patients have not shown significant pharmacokinetic differences versus healthy subjects with equivalent renal function. A population model developed from data in 79 patients with intra-abdominal infection or pneumonia, showed a dependence of the central volume on weight and the clearance on creatinine clearance and age.

Paediatric population

The pharmacokinetics in infants and children with infection at doses of 10, 20 and 40 mg/kg showed Cmax values approximating to those in adults following 500, 1000 and 2000 mg doses, respectively. Comparison showed consistent pharmacokinetics between the doses and half-lives similar to those observed in adults in all but the youngest subjects (<6 months t1/2 1.6 hours). The mean meropenem clearance values were 5.8 ml/min/kg (6-12 years), 6.2 ml/min/kg (2-5 years), 5.3 ml/min/kg (6-23 months) and 4.3 ml/min/kg (2-5 months). Approximately 60% of the dose is excreted in urine over 12 hours as meropenem with a further 12% as metabolite. Meropenem concentrations in the CSF of children with meningitis are approximately 20% of concurrent plasma levels although there is significant inter-individual variability.

The pharmacokinetics of meropenem in neonates requiring anti-infective treatment showed greater clearance in neonates with higher chronological or gestational age with an overall average half-life of 2.9 hours. Monte Carlo simulation based on a population PK model showed that a dose regimen of 20 mg/kg 8 hourly achieved 60%T>MIC for P. aeruginosa in 95% of pre-term and 91% of full term neonates.

Elderly

Pharmacokinetic studies in healthy elderly subjects (65-80 years) have shown a reduction in plasma clearance, which correlated with age-associated reduction in creatinine clearance, and a smaller reduction in non-renal clearance. No dose adjustment is required in elderly patients, except in cases of moderate to severe renal impairment.

Animal studies indicate that meropenem is well tolerated by the kidney. Histological evidence of renal tubular damage was seen in mice and dogs only at doses of 2000 mg/kg and above after a single administration and above and in monkeys at 500 mg/kg in a 7-day study.

Meropenem is generally well tolerated by the central nervous system. Effects were seen in acute toxicity studies in rodent at doses exceeding 1000 mg/kg.

The IV LD₅₀ of meropenem in rodents is greater than 2000 mg/kg.

In repeat dose studies of up to 6 months duration only minor effects were seen including a decrease in red cell parameters in dogs.

There was no evidence of mutagenic potential in a conventional test battery and no evidence of reproductive toxicity including teratogenic potential in studies in rats up to 750 mg/kg and in monkeys up to 360 mg/kg.

There was no evidence of increased sensitivity to meropenem in juveniles compared to adult animals. The intravenous formulation was well tolerated in animal studies.

The sole metabolite of meropenem had a similar profile of toxicity in animal studies.

Injection

Meropenem to be used for bolus intravenous injection should be constituted with sterile water for injection.

Infusion

For intravenous infusion meropenem vials may be directly constituted with 0.9% sodium chloride or 5% dextrose solutions for infusion.

Each vial is for single use only.

Standard aseptic techniques should be used for solution preparation and administration.

The solution should be shaken before use.

Any unused product or waste material should be disposed of in accordance with local requirements.