Winmero-1000

Winmero-1000

meropenem

Manufacturer:

Zeiss

Distributor:

Ambica
Full Prescribing Info
Contents
Meropenem trihydrate.
Description
Each vial contains: Sterile Meropenem trihydrate USP eq. to Meropenem 1 g, Sodium carbonate BP eq. to Sodium 90.2 mg.
Action
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 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 antibacterials agents when the mechanism involved include impermeability and/or an efflux pump(s).
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 meningitidis, 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.
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.
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.
Pharmacokinetics: 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.
Metabolism: 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. Fecal 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 hemodialysis 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 hemodialysis with clearance during hemodialysis 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.
Pediatrics: 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.
Indications/Uses
Meropenem is indicated for the treatment of the following infections in adults and children over 3 months of age: Severe pneumonia, including community acquired pneumonia and nosocomial 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 Meropenem may also be used in the management of neutropenic patients with fever that is suspected to be due to a bacterial infection.
Dosage/Direction for Use
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 or Acinetobacter spp.
Additional considerations for dosing are needed when treating patients with renal insufficiency (see further as follows).
Adults and Adolescents: See Table 1.

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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 adolescent should be adjusted when creatinine clearance is less than 51 mL/min. as shown as follows. There are limited data to support the application of these dose adjustments for a unit dose of 2 g. (See Table 2.)

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Meropenem is cleared by hemodialysis and hemofiltration. The required dose should be administered after completion of the hemodialysis 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.
Pediatric 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 as follows: See Table 3.

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Children over 50 kg body weight: The adult dose should be administered.
There is no experience in children with renal impairment.
Overdosage
Intentional overdosing of MEROPENEM FOR INJECTION USP is unlikely, although overdosing could occur during therapy particularly in patients with renal impairment. Limited post-marketing experience indicates that if adverse events occur following overdosage, 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 MEROPENEM FOR INJECTION USP and its metabolite.
Contraindications
MEROPENEM FOR INJECTION USP in contraindicated in patients who have demonstrated hypersensitivity to the active substance or any of the excipients. It is also contraindicated in patients who have hypersensitivity to any other carbapenem or B-lactam antibacterial agents.
Special Precautions
Patients who have a history of hypersensitivity to carbapenems, penicillins or other beta-lactam antibiotics may also be hypersensitive to MEROPENEM. As with all beta-lactam antibiotics rare hypersensitivity reactions have been reported (see ADVERSE REACTIONS).
As with other antibiotics, overgrowth of non-susceptible organisms may occur and repeated evaluation of each patient is necessary.
Rarely, pseudomembranous colitis has been reported with MEROPENEM FOR INJECTION USP as with virtually all antibiotics; therefore, its diagnosis should be considered in patients who develop diarrhoea in association with the use of MEROPENEM.
MEROPENEM FOR INJECTION USP may reduce serum valproic acid levels. Subtherapeutic levels may be reached in some patients. A positive direct or indirect Coombs test may develop.
Use in Patients with Renal insufficiency: See DOSAGE & ADMINISTRATION.
Use in Patients with Liver Disease: Patients with pre-existing liver disorders should have liver function monitored during treatment with MEROPENEM.
Effect on Ability to Drive or Operate Machinery: No data are available, but it is not anticipated that MEROPENEM FOR INJECTION USP will affect the ability to drive and operate machinery.
Use in Children: Efficacy and tolerability in infants under 3 months old have not been established; therefore, MEROPENEM FOR INJECTION USP is not recommended for use below this age.
Use In Pregnancy & Lactation
Use in Pregnancy: The safely of MEROPENEM FOR INJECTION USP in human pregnancy has not been established, although animal studies have not shown an adverse effect on the developing fetus. MEROPENEM FOR INJECTION USP should not be used in pregnancy unless the potential benefit justifies the potential risk to the foetus.
Meropenem is detectable at very low concentrations in animal breast milk. MEROPENEM FOR INJECTION USP should not be used in breast-feeding women unless the potential benefit justifies the potential risk to the baby.
Adverse Reactions
MEROPENEM FOR INJECTION USP is generally well tolerated. Adverse events rarely lead to cessation of treatment Serious adverse events are rare. (See Table 4.)

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Drug Interactions
Probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion of meropenem with the effect of increasing the elimination half-life and plasma concentration of meropenem. As the potency and duration of action of MEROPENEM FOR INJECTION USP dosed without probenecid are adequate the co-administration of probenecid with MEROPENEM FOR INJECTION USP is not recommended. The potential effect of MEROPENEM FOR INJECTION USP on the protein binding of other medicines or metabolism has not been studied. However, the protein binding is so low (approximately 2%) that no interactions with other compounds would be expected on the basis of this mechanism.
MEROPENEM FOR INJECTION USP has been administered concomitantly with many other medications without apparent adverse interaction. MEROPENEM FOR INJECTION USP may reduce serum valproic acid levels.
Subtherapeutic levels may be reached in some patients. However, no specific drug interaction studies other than with probenecid were conducted.
Caution For Usage
Direction for Reconstitution: 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 date available to support the administration of a 40 mg/kg dose in children as an intravenous bolus injection.
For injection (Sterile Water for Injection 10 mL per 500 mg). This provides an approximate available concentration of 50 rng/mL. Constituted solutions are clear or pale yellow.
MEROPENEM FOR INJECTION USP for intravenous infusion maybe directly constituted with a compatible infusion fluid and then further diluted (50 to 200 mL) with the compatible infusion fluid, as needed.
MEROPENEM FOR INJECTION USP is compatible with the following infusion fluids: 0.9% sodium chloride; 5% or 10% glucose; 5% glucose with 0.02% sodium bicarbonate; 5% glucose and 0.9% sodium chloride; 5% glucose with 0.02% sodium chloride; 5% glucose with 0.15% potassium chloride 2.5% and 10% mannitol; 5% glucose and Normosol-M; Also see SPECIAL PRECAUTIONS FOR STORAGE under STORAGE.
After reconstitution: Intravenous bolus injection administration: A solution for bolus injection is prepared by dissolving the drug product 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 12 hours under refrigerated conditions (2-8°C).
From a microbiological point of view, unless the method of opening/ reconstitution/ 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.
Intravenous infusion administration: A solution for infusion is prepared by dissolving the drug product in either 0.9% sodium chloride solution for infusion or 5% 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).
From a microbiological point of view, unless the method of opening/reconstitution/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.
Reconstituted solution of vials may be directly constituted with 0.9 % sodium chloride or 5% dextrose s 5% dextrose solution should be used immediately.
Special precautions for disposal and other handling: 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.
Incompatibilities: MEROPENEM FOR INJECTION USP is compatible with the solutions listed in SPECIAL PRECAUTIONS FOR STORAGE and should not be mixed with or physically added to solutions containing other medicines.
Single use only.
Parenteral drug product should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Storage
Store at temperatures not exceeding 25°C.
Store MEROPENEM FOR INJECTION USP powder for intravenous injection on infusion packs below 25°C.
To reduce microbiological hazard, solutions of MEROPENEM FOR INJECTION USP should be used as soon as practicable after reconstitution. If storage is necessary, hold at 2° to 8°C for not more than 24 hours, or the period shown in the following table, which ever is the lesser. (See Table 5.)

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Solutions of MEROPENEM FOR INJECTION USP should not be frozen.
Shelf-life: 24 months.
MIMS Class
ATC Classification
J01DH02 - meropenem ; Belongs to the class of carbapenems. Used in the systemic treatment of infections.
Presentation/Packing
Powd for inj (vial) 1 g x 1's.
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