Meronem

Meropenem.

Each 500-mg or 1-g vial contains meropenem trihydrate 570 or 1,140 mg equivalent to anhydrous meropenem 500 or 1,000 mg.
Each 500-mg or 1-g vial also contains anhydrous sodium carbonate 104 or 208 mg, respectively.
Each gram of meropenem (anhydrous potency) contains sodium 90 mg (3.9 mmol).
It contains anhydrous sodium carbonate as excipients.

Pharmacology: Pharmacodynamics: Meropenem is a carbapenem antibiotic for parenteral use, that is relatively stable to human dehydropeptidase-1 (DHP-1). It is structurally similar to imipenem.
Meropenem exerts its bactericidal action by interfering with bacterial cell wall synthesis. The ease with which it penetrates bacterial cell walls, its high level of stability to all serine β-lactamases and its marked affinity for the penicillin-binding proteins (PBPs) explain the potent bactericidal action of meropenem against a broad spectrum of aerobic and anaerobic bacteria. The bactericidal concentrations are generally within 1 doubling dilution of the minimum inhibitory concentrations (MICs).
Meropenem is stable in susceptibility tests, and these tests can be performed using normal routine methods. In vitro tests show that meropenem acts synergistically with various antibiotics. It has been demonstrated both in vitro and in vivo that meropenem has a post-antibiotic effect against gram-positive and gram-negative organisms.
Mechanisms of Resistance: Bacterial resistance to meropenem may result from ≥1 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 component and production of β-lactamases that can hydrolyse carbapenems.
Localised clusters of infections due to carbapenem-resistant bacteria have been reported in some regions.
The susceptibility to Meronem of a given clinical isolate should be determined by standard methods. Interpretations of test results should be made in accordance with local infectious diseases and clinical microbiology guidelines.
The antibacterial spectrum of Meronem includes the following species, based on clinical experience and the therapeutic guidelines.
Commonly Susceptible Species: Gram-Positive Aerobes: Enterococcus faecalis (note that E. faecalis can naturally display intermediate susceptibility), Staphylococcus aureus [methicillin-susceptible strains only: Methicillin-resistant staphylococci including methicillin resistant Staphylococcus aureus (MRSA) are resistant to meropenem], Staphylococcus spp. including Staphylococcus epidermidis [methicillin-susceptible strains only: Methicillin-resistant staphylococci including methicillin resistant Staphylococcus epidermis (MRSE) are resistant to meropenem], Streptococcus agalactiae (Group B streptococcus), Streptococcus milleri group (S. anginosus, S. constellatus and S. intermedius), Streptococcus pneumoniae, Streptococcus pyogenes (Group A streptococcus).
Gram Negative Aerobes: Citrobacter freundii, Citrobacter koseri, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Morganella morganii, Neisseria meningitidis, Proteus mirabilis, Proteus vulgaris, Serratia marcescens.
Gram Positive Anaerobes: Clostridium perfringens, Peptoniphilus asaccharolyticus, Peptostreptococcus spp (including P. micros, P anaerobius, P. magnus).
Gram Negative Anaerobes: Bacteroides caccae, Bacteroides fragilis, Prevotella bivia, Prevotella disiens.
Species for Which Acquired Resistance May Be a Problem: Gram Positive Aerobes: Enterococcus faecium (E. faecium can naturally display intermediate susceptibility even without acquired resistance mechanisms.
Species for Which Acquired Resistance May Be a Problem: Gram Negative Aerobes: Acinetobacter spp, Burkholderia cepacia, Pseudomonas aeruginosa.
Inherently Resistant Organisms: Gram Negative Aerobes: Stenotrophomonas maltophilia, Legionella spp.
Other Inherently Resistant Organisms: Chlamydophila pneumoniae, Chlamydophila psittaci, Coxiella burnetii, Mycoplasma pneumoniae.
The published medical microbiology literature describes in vitro meropenem-susceptibilities of many other bacterial species. However, the clinical significance of such in vitro findings is uncertain. Advice on the clinical significance of in vitro findings should be obtained from local infectious diseases and clinical microbiology experts and local professional guidelines.
Meropenem is active in vitro against many strains resistant to other β-lactam antibiotics. This is explained in part by enhanced stability to β-lactamases. Activity in vitro against strains resistant to unrelated classes of antibiotics eg, aminoglycosides or quinolones is common.
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.
Stenotrophomonas maltophilia, Enterococcus faecium and methicillin-resistant staphylococci have been found to be resistant to meropenem.
Pharmacokinetics: In healthy subjects the mean plasma half-life is approximately 1 hr; the mean volume of distribution is approximately 0.25 L/kg and the mean clearance is 239 mL/min at 500 mg falling to 205 mL/min at 2 g. Doses of 500, 1,000 and 2,000 mg doses infused over 30 mins give mean C_max values of approximately 23, 49 and 115 mcg/mL respectively, corresponding AUC values were 39.3, 62.3 and 153 mcg.h/mL. After infusion over 5 mins C_max values are 52 and 112 mcg/mL after 500 and 1,000 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 1,000 mg 8 hourly post-surgically for intra-abdominal infections showed a comparable C_max and half-life to normal subjects but a greater volume of distribution 27l.
Distribution: The average plasma protein binding of meropenem was approximately 2% and was independent of concentration. 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.
Metabolism: Meropenem is metabolised by hydrolysis of the β-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 hrs. 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: Pharmacokinetic studies in patients with renal insufficiency have shown the plasma clearance of meropenem correlates with creatinine clearance (CrCl). Dosage adjustments are necessary in subjects with renal impairment.
Hepatic Insufficiency: A study in patients with alcoholic cirrhosis has shown no effect of liver disease on the pharmacokinetics of meropenem after repeated doses.
Children: Studies in children have shown that the pharmacokinetics of Meronem IV in children is similar to those in adults. The elimination half-life for meropenem was approximately 1.5-2.3 hrs in children <2 years and the pharmacokinetics is linear over the dose range of 10-40 mg/kg.
Elderly: Pharmacokinetic studies in the elderly subjects (65-80 years) have shown a reduction in plasma clearance which correlated with age-associated reduction in CrCl and a smaller reduction in non-renal clearance. No dose adjustment is required in elderly patients with normal renal function or CrCl >50 mL/min (see Dosage & Administration).
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).
Meropenem is generally well tolerated by the central nervous system (CNS). Effects were seen only at very high doses of ≥2,000 mg/kg.
The IV LD₅₀ of meropenem in rodents is >2,000 mg/kg. In repeat dose studies (up to 6 months duration), 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 rats was 120 mg/kg].
There was an increased incidence of abortions at 500 mg/kg in a preliminary study in monkeys.
There was no evidence of increased sensitivity to meropenem in juveniles compared to adult animals. The IV formulation was well tolerated in animal studies.
The sole metabolite of meropenem had a similar profile toxicity in animal studies.

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; gynecological infections eg, endometritis; skin and skin structure infections; meningitis; septicemia.
Empiric treatment for presumed infections in adult patients with febrile neutropenia, used as monotherapy or in combination with antiviral or antifungal agents.
Meronem has proved efficacious alone or in combination with other antimicrobial agents in the treatment of polymicrobial infections.
There is no experience in pediatric patients with neutropenia or primary or secondary immunodeficiency.

The dosage and duration of therapy should be established depending on type and severity of infection and the condition of the patient.
Adults: Treatment of Pneumonia, Urinary Tract Infections, Gynecological Infections eg, Endometritis, Skin and Skin Structure Infections: Recommended Daily Dosage: 500-mg IV every 8 hrs.
Treatment of Nosocomial Pneumonias, Peritonitis, Presumed Infections in Neutropenic Patients and Septicemia: 1 g IV every 8 hrs.
Meningitis: Recommended Dosage: 2 g every 8 hrs.
When treating infections known or suspected to be caused by Pseudomonas aeruginosa, a dose of at least 1 g every 8 hours in adults (maximum approved dose is 6 g daily given in 3 divided doses) and a dose of at least 20 mg/kg every 8 hours in children (maximum approved dose is 120 mg/kg daily given in 3 divided doses) are recommended. Regular sensitivity testing is recommended when treating Pseudomonas aeruginosa infection.
Adults with Impaired Renal Function: Dosage should be reduced in patients with CrCl <51 mL/min, as scheduled as follows. (See table.)


Click on icon to see table/diagram/image


Meropenem is cleared by hemodialysis and hemofiltration; if continued treatment with Meronem is necessary, the unit dose based on the infection type and severity is recommended at the completion of the hemodialysis procedure to re-institute effective treatment.
There is no experience with peritoneal dialysis.
Adults with Hepatic Insufficiency: No dosage adjustment is necessary in patients with hepatic impairment.
Children >3 months up to 12 years: Recommended Dose: 10-20 mg/kg every 8 hrs depending on type and severity of infection, the known or suspected susceptibility of the pathogens and the condition of the patient.
Children >50 kg body weight: Adult dosage should be used.
Meningitis: Recommended Dose: 40 mg/kg every 8 hrs.
There is no experience in children with renal impairment.
Elderly: No dosage adjustment is required for the elderly with normal renal function or creatinine clearance values >50 mL/min.
Administration: Meronem should be given as an IV bolus injection over approximately 5 min or by IV infusion over approximately 15-30 min. There is limited safety data available to support the administration of a 40 mg/kg bolus dose.

Intentional overdosing of Meronem is unlikely, although overdosing could occur particularly in patients with renal impairment. Limited post-marketing experience indicates that if adverse events occur following over dosage, they are consistent with the adverse event profile described in Adverse Reactions, are generally mild in severity and resolve on withdrawal or dose reduction. Symptomatic treatments should be considered.
In normal individuals rapid renal elimination will occur. Hemodialysis will remove Meronem IV and its metabolite.

Patients who have demonstrated hypersensitivity to Meronem.

Patients who have a history of hypersensitivity to carbapenems, penicillins or other β-lactam antibiotics may also be hypersensitive to Meronem IV. As with all β-lactam antibiotics, rare hypersensitivity reactions (serious and occasionally fatal) have been reported (see Adverse Reactions).
Severe cutaneous adverse reactions (SCAR), such as Steven-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme (EM) and acute generalized exanthematous pustulosis (AGEP) have been reported in patients receiving Meronem IV. If signs and symptoms suggestive of these reactions appear, meropenem should be withdrawn immediately and alternative treatment should be considered.
As with other antibiotics, overgrowth of nonsusceptible organisms may occur and repeated evaluation 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 gastrointestinal complaints, particularly colitis.
It is important to consider the diagnosis of pseudomembranous colitis in the case of patients who develop diarrhea 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 concomitant use of valproic acid/sodium valproate and Meronem is not recommended.
Meronem IV may reduce serum valproic acid levels. Subtherapeutic levels may be reached in some patients (see Interactions).
Effects on the 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.
Use in children: Efficacy and tolerability in infants <3 months have not been established; therefore, Meronem is not recommended for use below this age.
Renal Impairment: See Dosage & Administration.
Hepatic Impairment: Patients with preexisting liver disorders should have liver function monitored during treatment with Meronem IV.
A positive direct or indirect Coombs test may develop.

Use in pregnancy: The safety of Meronem in human pregnancy has not been established although animal studies have not shown an adverse effect on the developing fetus.
Meronem should not be used in pregnancy unless the potential benefit justifies the potential risk to the fetus.
Use in lactation: Meropenem has been reported to be excreted in human milk. Meronem should not be used in breastfeeding women unless the potential benefit justifies the potential risk to the baby.

Meronem 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. Their frequency is presented as follows. 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 adverse reactions 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%).
Frequency of Adverse Reactions (Data Derived From Clinical Trial Data Sources): Infections and Infestations: Uncommon: Oral and vaginal candidiasis.
Blood and Lymphatic System Disorders: Common: Thrombocythaemia. Uncommon: Eosinophilia, thrombocytopenia, leucopenia, neutropenia.
Nervous System Disorders: Common: Headache. Uncommon: Paraesthesiae. Rare: convulsions.
Gastrointestinal Disorders: Common: Diarrhoea, vomiting, nausea.
Hepatobiliary Disorders: Common: Increased alanine aminotransferase, aspartate aminotransferase, blood alkaline phosphatase, blood lactate dehydrogenase, γ-glutamyltransferase. Uncommon: Increased blood bilirubin.
Skin and Subcutaneous Tissue Disorders: Common: Rash, pruritis. Uncommon: Urticaria.
General Disorders and Administration Site Conditions: Common: Inflammation, pain. Uncommon: Thrombophlebitis.
The following adverse reactions have been identified from post-marketing clinical trials and spontaneous reports. Their frequency is presented as follows: 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 adverse reactions 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%).
Reporting Rate of Adverse Reactions (Data Derived From a Combination of Post-Marketing Clinical Trial and Spontaneous Sources): Blood and Lymphatic System Disorders: Rare: Agranulocytosis. Very Rare: Hemolytic anemia.
Immune System Disorders: Very Rare: Angioedema, manifestations of anaphylaxis.
Gastrointestinal Disorders: Very Rare: Pseudomembranous colitis.
Skin and Subcutaneous Tissue Disorders: Very Rare: Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme.

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 dosed without probenecid are adequate, the co-administration of probenecid with Meronem is not recommended.
The potential effect of Meronem on the protein-binding of other drugs or metabolism has not been studied. However, the protein-binding of Meronem is low that no interactions with other compounds would be expected on the basis of this mechanism.
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 2 days. Due to the rapid onset and the extent of the decrease, co-administration of Meronem in patients stabilised on valproic acid is not considered to be manageable and therefore, should be avoided (see Precautions).
Meronem has been administered concomitantly with other medications without adverse pharmacological interactions. However, no specific drug interactions studies other than probenecid were conducted.
Incompatibilities: Meronem should not be mixed with or physically added to solutions containing other drugs.

Constitution and Compatibility: Meronem IV to be used for bolus IV injection should be constituted with sterile water for injections (10 mL/500 mg). This provides an approximate available concentration of 50 mg/mL. Constituted solutions are clear or pale yellow.
For IV infusion Meronem vials may be directly constituted with a compatible infusion fluid (see Storage) and then further diluted with the compatible infusion fluid, as needed.
Freshly prepared solutions of Meronem IV should be used whenever possible. However, constituted solutions of Meronem IV maintain satisfactory potency at room temperature (15-25°C) or under refrigeration (4°C).
Meronem should not be mixed with or physically added to solutions containing other drugs. Solutions of Meronem should not be frozen.
Instructions for Use/Handling: Standard aseptic technique should be employed during constitution. Shake constituted solution before use.
All vials are for single use only.

Do not store above 30°C. Do not freeze.
A solution for bolus injection is prepared by dissolving the drug product Meronem 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 hrs at up to 25°C or 16 hrs under refrigerated conditions (2-8º C).
A solution for infusion is prepared by dissolving the drug product Meronem 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 hrs at up to 25°C or 15 hrs under refrigerated conditions (2-8°C). Constituted solutions of Meronem 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.

Other Beta-Lactams

J01DH02 - meropenem ; Belongs to the class of carbapenems. Used in the systemic treatment of infections.

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