Meronem

Meronem

meropenem

Manufacturer:

Sumitomo Dainippon Pharma

Distributor:

Zuellig Pharma

Marketer:

Zuellig Pharma
Full Prescribing Info
Contents
Meropenem trihydrate.
Description
Active ingredient: Meronem IV 500 mg: Meropenem trihydrate 570 mg; equivalent to anhydrous meropenem 500 mg.
Meronem IV 1000 mg: Meropenem trihydrate 1140 mg;
equivalent to anhydrous meropenem 1000 mg.
Excipients/Inactive Ingredients: Meronem IV 500 mg: Anhydrous sodium carbonate 104 mg.
Meronem IV 1000 mg: Anhydrous sodium carbonate 208 mg.
For each gram of meropenem (anhydrous potency) the vial contains 90 mg (3.9 mmol) of sodium.
Action
Pharmacotherapeutic group: antibacterials for systemic use, carbapenems. ATC code: J01DH02.
Pharmacology: Pharmacodynamics: Mode of action: Meropenem exerts its bactericidal activity by inhibiting bacterial cell wall synthesis in Gram-positive and Gram-negative bacteria through binding to multiple 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.
Pharmacokinetics: A 30 minute intravenous infusion of a single dose of Meronem in healthy volunteers results in peak plasma levels of approximately 11 μg/mL for the 250 mg dose, 23 μg/mL for the 500 mg dose and 49 μg/mL for the 1g dose.
However, there is no absolute pharmacokinetic proportionality with the administered dose both as regards Cmax and AUC. Furthermore, a reduction in plasma clearance from 239 to 205 mL/min for the range of dosage 500 mg to 2 g has been observed.
A 5 minute intravenous bolus injection of Meronem IV in healthy volunteers results in peak plasma levels of approximately 52 μg/mL for the 500 mg dose and 112 μg/mL for the 1g dose.
After an IV dose of 500 mg, plasma levels of meropenem decline to values of 1 μg/mL or less, 6 hours after administration.
When multiple doses are administered at 8 hourly intervals to subjects with normal renal function, accumulation of meropenem does not occur.
In subjects with normal renal function, meropenem's elimination half-life is approximately 1 hour.
Plasma protein binding of meropenem is approximately 2%.
Approximately 70% of the administered dose is recovered as unchanged meropenem in the urine over 12 hours, after which little further urinary excretion is detectable. Urinary concentrations of meropenem in excess of 10 μg/mL are maintained for up to 5 hours after the administration of a 500 mg dose. No accumulation of meropenem in plasma or urine was observed with regimens using 500 mg administered every 8 hours or 1g administered every 6 hours in volunteers with normal renal function.
The only metabolite of meropenem is microbiologically inactive.
Meropenem penetrates well into most body fluids and tissues including cerebrospinal fluid of patients with bacterial meningitis, achieving concentrations in excess of those required to inhibit most bacteria.
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.
Pharmacokinetic studies in patients with renal insufficiency have shown the plasma clearance of meropenem correlates with creatinine clearance. Dosage adjustments are necessary in subjects with renal impairment.
Pharmacokinetic studies in the elderly have shown a reduction in plasma clearance of meropenem which correlated with age-associated reduction in creatinine clearance.
Pharmacokinetic studies in patients with liver disease have shown no effects of liver disease on the pharmacokinetics of meropenem.
Toxicology: Preclinical Safety Data: Animal studies indicate that meropenem is well tolerated by the kidney. In animal studies meropenem has shown nephrotoxic effects, only at high dose levels (500 mg/kg).
Effects on the CNS; convulsions in rats and vomiting in dogs, were seen only at high doses (>2000 mg/kg).
For an IV dose the LD50 in rodents is greater than 2000 mg/kg. In repeat dose studies (up to 6 months) only minor effects were seen including a small decrease in red cell parameters and an increase in liver weight in dogs treated with doses of 500 mg/kg.
There was no evidence of mutagenic potential in the 5 tests conducted and no evidence of reproductive and teratogenic toxicity in studies at the highest possible doses in rats and monkeys; the no effect dose level of a (small) reduction in F1 body weight in rat was 120 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.
Microbiology: Mechanisms of resistance: Bacterial resistance to meropenem may result from one or more factors: decreased permeability of the outer membrane of Gram-negative bacteria (due to diminished production of porins); reduced affinity of the target PBPs; increased expression of efflux pump components, and 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 antibacterials 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 as follows. (See Table 1.)

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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. (See Table 2.)

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Indications/Uses
Meronem IV is indicated for treatment, in adults and children, of the following infections caused by single or multiple bacteria sensitive to meropenem. Pneumonias and Nosocomial pneumonias; Urinary Tract Infections; Intra-abdominal Infections; Gynaecological Infections, such as endometritis and pelvic inflammatory disease; Bacterial Meningitis; Septicaemia; Empiric treatment, for presumed infections in patients with febrile neutropenia, used as monotherapy or in combination with anti-viral or anti-fungal agents.
Meronem IV has proved efficacious alone or in combination with other antimicrobial agents in the treatment of polymicrobial infections.
Dosage/Direction for Use
Adults: The dosage and duration of therapy shall be established depending on type and severity of infection and the condition of the patient.
The recommended daily dosage is as follows: 500 mg IV every 8 hours in the treatment of pneumonia, UTI, gynaecological infections such as endometritis.
1 g IV every 8 hours in the treatment of hospital acquired pneumonias, peritonitis, presumed infections in febrile neutropenic patients, septicaemia.
In meningitis the recommended dosage is 2 g every 8 hours.
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 nosocomial infections due to Pseudomonas aeruginosa.
Regular sensitivity testing is recommended when treating Pseudomonas aeruginosa infection.
There are limited safety data available to support the administration of a 2 g dose in adults as an intravenous bolus injection.
Dosage Schedule for Adults with Impaired Renal Function: Dosage should be reduced in patients with creatinine clearance less than 51 mL/min, as scheduled as follows. There are limited data to support the application of these dose adjustments for a unit dose of 2 g. (See Table 3.)

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Meronem IV is cleared by haemodialysis and haemofiltration; if continued treatment with Meronem IV is necessary, it is recommended that the unit dose (based on the type and severity of infection) is administered at the completion of the haemodialysis procedure to restore therapeutically effective plasma concentrations.
There is no experience with the use of Meronem IV in patients under peritoneal dialysis.
Dosage in Adults with Hepatic Insufficiency: No dosage adjustment is necessary in patients with hepatic insufficiency (see Precautions).
Elderly Patients: No dosage adjustment is required for the elderly with normal renal function or creatinine clearance values above 50 mL/min.
Children: For children over 3 months and up to 12 years of age the recommended dose is 10 - 20 mg/kg every 8 hours depending on type and severity of infection, susceptibility of the pathogen and the condition of the patient. In children over 50 kg weight, adult dosage should be used.
In meningitis the recommended dose is 40 mg/kg every 8 hours.
Febrile episodes in neutropenic patients-the dose should be 20 mg/kg every 8 hours.
There is no experience in children with renal impairment.
There are limited safety data available to support the administration of a 40 mg/kg dose in children as an intravenous bolus injection.
Method of Administration: Meronem IV can be given as an intravenous bolus injection over approximately 5 minutes or by intravenous infusion over approximately 15 to 30 minutes using the specific available presentations.
Meronem IV to be used for bolus intravenous injection should be constituted with sterile Water for Injections (5 mL per 250 mg Meropenem). This provides an approximate concentration of 50 mg/mL. Constituted solutions are clear, and colourless or pale yellow.
Meronem IV for intravenous infusion may be constituted with compatible infusion fluids (50 to 200 mL) (see Incompatibilities under Cautions for Usage and Storage).
Overdosage
Accidental overdosage could occur during therapy, particularly in patients with renal impairment. Treatment of overdosage should be symptomatic. In normal individuals rapid renal elimination will occur; in subjects with renal impairment haemodialysis will remove meropenem and its metabolite.
Contraindications
Meronem IV is contraindicated in patients who have demonstrated hypersensitivity to this product.
Special Precautions
There is some clinical and laboratory evidence of partial cross-allergenicity between other carbapenems and beta-lactam antibiotics, penicillins and cephalosporins. Serious and occasionally fatal hypersensitivity reactions (including anaphylactoid and severe cutaneous adverse reactions (SCAR)) have been reported in patients receiving therapy with beta-lactams. Before initiating therapy with Meronem IV, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, carbapanems or other beta-lactam agents. If an allergic reaction occurs, Meronem IV must be discontinued immediately and appropriate alternative therapy instituted.
SCAR, such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme (EM) and acute generalised exanthematous pustulosis (AGEP) have been reported in patients receiving Meronem IV (See "Adverse Reactions"). If signs and symptoms suggestive of these reactions appear, meropenem should be withdrawn immediately and an alternative treatment should be considered.
Use of Meronem IV in patients with hepatic disease should be made with careful monitoring of transaminase and bilirubin levels.
As with other antibiotics, overgrowth of non-susceptible organisms may occur and, therefore, continuous monitoring of each patient is necessary.
Use in infections caused by methicillin resistant staphylococci is not recommended.
Rarely, pseudomembranous colitis has been reported on Meronem IV as with practically all antibiotics and may vary in severity from slight to life-threatening. Therefore, antibiotics should be prescribed with care for individuals with a history of gastro-intestinal complaints, particularly colitis.
It is important to consider the diagnosis of pseudomembranous colitis in the case of patients who develop diarrhoea in association with the use of Meronem IV. Although studies indicate that a toxin produced by Clostridium difficile is one of the main causes of antibiotic-associated colitis, other causes should be considered.
The co-administration of Meronem IV with potentially nephrotoxic drugs should be considered with caution. (For dosage see "Dosage & Administration").
The concomitant use of valproic acid/sodium valproate and Meronem IV is not recommended. Meronem IV may reduce serum valproic acid levels. Subtherapeutic levels may be reached in some patients (see "Interactions").
Effect on Ability to Drive or Operate Machinery: No studies 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 Meronem IV.
Use in Children: Efficacy and tolerability in infants under 3 months old have not been established; therefore, Meronem IV is not recommended for use below this age. There is no experience in children with altered hepatic or renal function.
Use In Pregnancy & Lactation
Pregnancy: The safety of Meronem IV in human pregnancy has not been evaluated. Animal studies have not shown any adverse effect on the developing foetus. The only adverse effect observed in animal reproductive studies was an increased incidence of abortions in monkeys at 13 times the expected exposure in man. Meronem IV should not be used in pregnancy unless the potential benefit justifies the potential risk to the foetus. In every case, it should be used under the direct supervision of the physician.
Lactation: Meropenem has been reported to be excreted in human milk. Meronem IV should not be used in breast-feeding women unless the potential benefit justifies the potential risk to the baby.
Adverse Reactions
Meronem IV is generally well tolerated. Adverse reactions rarely lead to cessation of treatment. Serious adverse reactions are rare.
The following adverse reactions have been identified following clinical studies with Meronem IV. Their frequency is presented in Table 4 Frequency of Adverse Reactions (data derived from clinical trial data sources) using CIOMS III frequency classification and then listed by MedDRA SOC and at the preferred level. Frequencies of occurrence of undesirable effects are defined as: very common (≥1/10; ≥10%); common (≥1/100 to <1/10; ≥1% to <10%); uncommon (≥1/1,000 to <1/100; ≥0.1% to <1%); rare (≥1/10,000 to <1/1,000; ≥0.01% to <0.1%); very rare (<1/10,000; <0.01%). (See Table 4.)

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The following adverse reactions have been identified from post-marketing clinical trials and spontaneous reports. Their frequency is presented in Table 5: Reporting Rate of Adverse Reactions (data derived from a combination of post-marketing clinical trial and spontaneous sources) using CIOMS III frequency classification and then listed by MedDRA SOC and at the preferred level. Frequencies of occurrence of undesirable effects are defined as: very common (≥1/10; ≥10%); common (≥1/100 to <1/10; ≥1% to <10%); uncommon (≥1/1,000 to <1/100; ≥0.1% to <1%); rare (≥1/10,000 to <1/1,000; ≥0.01% to <0.1%); very rare (<1/10,000; <0.01%), not known (cannot be estimated from the available data). (See Table 5.)

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Drug Interactions
Probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion, with the effect of increasing the elimination half-life and plasma concentration of meropenem. As the potency and duration of action of Meronem IV dosed without probenecid are adequate, the co-administration of probenecid with Meronem IV is not recommended.
The potential effect of Meronem IV on the protein binding of other drugs or metabolism has not been studied. The protein binding of Meronem IV is low (approximately 2%) and, therefore, no interactions with other compounds based on displacement from plasma proteins would be expected.
Meronem IV may reduce serum valproic acid levels. Subtherapeutic levels may be reached in some patients.
Decreases in blood levels of valproic acid have been reported when it is co-administered with carbapenem agents resulting in a 60-100% decrease in valproic acid levels in about two days. Due to the rapid onset and the extent of the decrease, co-administration of Meronem IV in patients stabilised on valproic acid is not considered to be manageable and therefore should be avoided (see Precautions).
Meronem IV has been administered concomitantly with many other medications without apparent adverse interaction. However, no specific drug interaction studies other than probenecid were conducted.
Caution For Usage
Instructions for Use/Handling: Refer to Dosage & Administration. Standard aseptic technique should be employed during constitution. Shake constituted solution before use.
All vials are for single use only.
Incompatibilities: Meronem IV should not be mixed with or added to other drugs.
Meronem IV is compatible with the following infusion fluids: 0.9% Sodium Chloride solution; 5% or 10% Glucose solution; 5% Glucose solution with 0.02% Sodium Bicarbonate; 0.9% Sodium Chloride and 5% Glucose solution; 5% Glucose with 0.225% Sodium Chloride solution; 5% Glucose with 0.15% Potassium Chloride solution; Mannitol 2.5% or 10% solution.
Storage
Do not store over 30°C.
Do not freeze.
A solution for bolus injection is prepared by dissolving the drug product Meronem IV in water for injection to a final concentration of 50 mg/mL. Chemical and physical in-use stability for a prepared solution for bolus injection has been demonstrated for 3 hours at up to 25°C or 16 hours under refrigerated conditions (2-8°C).
A solution for infusion is prepared by dissolving the drug product Meronem IV in either 0.9% sodium chloride solution for infusion or 5% glucose (dextrose) solution for infusion to a final concentration of 1 to 20 mg/mL. Chemical and physical in-use stability for a prepared solution for infusion using 0.9% sodium chloride solution has been demonstrated for 3 hours at up to 25°C or 24 hours under refrigerated conditions (2-8°C). Constituted solutions of Meronem IV in 5% glucose (dextrose) solution should be used immediately.
The constituted solutions should not be frozen.
From a microbiological point of view, unless the method of opening/constitution/dilution precludes the risk of microbiological contamination, the product should be used immediately.
If not used immediately, in-use storage times and conditions are the responsibility of the user.
MIMS Class
ATC Classification
J01DH02 - meropenem ; Belongs to the class of carbapenems. Used in the systemic treatment of infections.
Presentation/Packing
Powd for inj/infusion (vial) (sterile, white powd) 500 mg x 20 mL x 10's. 1 g x 30 mL x 10's.
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