Meropenem

383.46

383.46

1806241-263-5

YOP6PX0BAO

DTXSID7045526

C61833

J01DH02|J - Antiinfectives for systemic use

29419000

136

-2.4

Solid

1.4±0.1 g/cm3

627.4°C at 760 mmHg

333.2±31.5 °C

1.639

Sparingly soluble with water.

6.85X10-18 mm Hg at 25 deg C (est)

Henry's Law constant = 3.43X10-23 atm-cu m/mol at 25 °C (est)

192.42 Ų [M-H]-

White to pale yellow crystalline powder. Sparingly soluble in water; very slightly soluble in hydrated ethanol /Meropenem trihydrate/|The solution varies from colorless to yellow depending on the concentration. The pH of freshly constituted solutions is between 7.3 and 8.3. Meropenem is soluble in 5% monobasic potassium phosphate solution ... and practically insoluble in acetone or ether. /Meropenem trihydrate/|Hydroxyl radical reaction rate constant = 1.81X10-10 cu cm/molec-sec at 25 °C (est)

36/37/38

26-37/39

Xi

Meropenem infusion vials constituted with Sodium Chloride Injection 0.9% (Meropenem concentrations ranging from 2.5 to 50 mg/mL) are stable for up to 2 hours at controlled room temperature 15-25 deg C (59-77 deg F) or for up to 18 hours at 4 deg C (39 deg F). Infusion vials of Meropenem constituted with Dextrose Injection 5% (Meropenem concentrations ranging from 2.5 to 50 mg/mL) are stable for up to 1 hour at controlled room temperature 15-25 deg C (59-77 deg F) or for up to 8 hours at 4 deg C

P261, P264, P271, P272, P280, P285, P302+P352, P304+P340, P304+P341, P305+P351+P338, P312, P321, P332+P313, P333+P313, P337+P313, P342+P311, P362, P363, P403+P233, P405, P501

H315

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including meropenem, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

|Danger|H315 (76.92%): Causes skin irritation [Warning Skin corrosion/irritation]|P261, P264, P271, P272, P280, P285, P302+P352, P304+P340, P304+P341, P305+P351+P338, P312, P321, P332+P313, P333+P313, P337+P313, P342+P311, P362, P363, P403+P233, P405, and P501|Aggregated GHS information provided by 13 companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Respiratory Protection: Use a NIOSH approved respirator, if it is determined to be necessary by an industrial hygiene survey involving air monitoring. In the event that a respirator is not required, an approved dust mask should be used. Gloves: Chemically compatible. Eye Protection: Safety Glasses. Protective Clothing: Protect exposed skin.

This material is assumed to be combustible.

As with all fires, evacuate personnel to a safe area. Firefighters should use self-contained breathing equipment and protective clothing.|Water spray, dry chemical, carbon dioxide or foam as appropriate for surrounding fire and materials.

Spill Response: Wear approved respiratory protection, chemically compatible gloves and protective clothing. Wipe up spillage or collect spillage using a high efficiency vacuum cleaner. Avoid breathing dust. Place spillage in appropriately labelled container for disposal. Wash spill site.

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.|Engineering controls such as exhaust ventilation are recommended.|As a general rule, when handling USP Reference Standards avoid all contact and inhalation of dust, mists, and/or vapors associated with the material. Wash thoroughly after handling.|As with all dry powders it is advisable to ground mechanical equipment in contact with dry material to dissipate the potential buildup of static electricity.

In mice and rats, large intravenous doses of meropenem (2200-4000 mg/kg) have been associated with ataxia, dyspnea, convulsions, and mortalities.

Serum aminotransferase elevations have been reported in 1% to 6% of recipients of intravenous meropenem when given for up to 14 days. These elevations are usually transient, mild and asymptomatic; and rarely require dose adjustment. Meropenem has also been linked to rare cases of cholestatic jaundice that usually arises after 1 to 3 weeks of therapy. Immunoallergic features may be present, but are rarely prominent. Autoantibodies are rare. Most cases are mild and self-limited, but at least one instance of vanishing bile duct syndrome related to meropenem therapy has been published (Case 1). Meropenem has not been reported to cause acute liver failure.

Case reports in the literature have shown that co-administration of carbapenems, including meropenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. Although the mechanism of this interaction is unknown, data from in vitro and animal studies suggest that carbapenems may inhibit the hydrolysis of valproic acid's glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the serum concentrations of valproic acid. If administration of Meropenem for injection is necessary, then supplemental anti-convulsant therapy should be considered|Probenecid competes with meropenem for active tubular secretion, resulting in increased plasma concentrations of meropenem. Co-administration of probenecid with meropenem is not recommended.

Meropenem for injection (IV) is contraindicated in patients with known hypersensitivity to any component of this product or to other drugs in the same class or in patients who have demonstrated anaphylactic reactions to beta-lactams.

Approximately 2%.

For use as single agent therapy for the treatment of the following infections when caused by susceptible isolates of the designated microorganisms: complicated skin and skin structure infections due to Staphylococcus aureus (b-lactamase and non-b-lactamase producing, methicillin-susceptible isolates only), Streptococcus pyogenes, Streptococcus agalactiae, viridans group streptococci, Enterococcus faecalis (excluding vancomycin-resistant isolates), Pseudomonas aeruginosa, Escherichia coli, Proteus mirabilis, Bacteroides fragilis and Peptostreptococcus species; complicated appendicitis and peritonitis caused by viridans group streptococci, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroides fragilis, B. thetaiotaomicron, and Peptostreptococcus species. Also for use in the treatment of bacterial meningitis caused by Streptococcus pneumoniae, Haemophilus influenzae (b-lactamase and non-b-lactamase-producing isolates), and Neisseria meningitidis.|FDA Label|Treatment of bacterial sepsis, Treatment of bacterial meningitis

Meropenem is a carbapenem antibiotic with broad spectrum of activity that is administered intravenously and used for severe bacterial infections due to sensitive agents. Meropenem is a common cause of mild transient aminotransferase elevations and can rarely result in clinically apparent, cholestatic liver injury.

Antiinfective Agents

Anti-Bacterial Agents|Meropenem is used for the treatment of intra-abdominal infections, including complicated appendicitis and peritonitis, caused by susceptible bacteria. The drug may be used as monotherapy for the treatment of intra-abdominal infections caused by susceptible viridans streptococci, Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa, Bacteroides fragilis, B. thetaiotaomicron, or Peptostreptococcus. Because meropenem has a broad spectrum of antibacterial activity, the drug may be used empirically to treat intra-abdominal infections before identification of the causative organism. /Included in US product labeling/|Meropenem is used for the treatment of bacterial meningitis caused by susceptible Streptococcus pneumoniae, Haemophilus influenzae (including beta-lactamase-producing strains), or Neisseria meningitidis in children 3 months of age and older. /Included in US product labeling/|The drug also is used in the treatment of meningitis in adults. /NOT included in US product labeling/|For more Therapeutic Uses (Complete) data for Meropenem (20 total), please visit the HSDB record page.

Serious and occasionally fatal hypersensitivity reactions (e.g., anaphylaxis) reported with beta-lactams. If hypersensitivity occurs, discontinue meropenem and institute appropriate therapy as indicated (e.g., epinephrine, corticosteroids, and maintenance of an adequate airway and oxygen).|Adverse effects reported in 1% or more of patients receiving meropenem including GI effects (diarrhea, nausea, vomiting, constipation), local reactions (pain and inflammation at injection site, phlebitis/thrombophlebitis), headache, anemia, rash, pruritus, sepsis, apnea, shock, glossitis, and oral candidiasis.|Seizures and other adverse CNS effects reported during meropenem therapy, especially in those with underlying CNS disorders (e.g., brain lesions, history of seizures), bacterial meningitis, or compromised renal function. Do not exceed recommended dosage, especially in those with known factors that predispose to seizures. Anticonvulsant therapy should be continued in those with known seizure disorders. If focal tremors, myoclonus, or seizures occur, evaluate the patient neurologically, initiate anticonvulsant therapy if necessary, and determine whether meropenem dosage should be decreased or the drug discontinued.|Partial cross-allergenicity among beta-lactam antibiotics, including penicillins, cephalosporins, and other beta-lactams. Prior to initiation of meropenem therapy, make careful inquiry concerning previous hypersensitivity reactions to meropenem, cephalosporins, penicillins, or other drugs.|For more Drug Warnings (Complete) data for Meropenem (8 total), please visit the HSDB record page.

Meropenem is a broad-spectrum carbapenem antibiotic. It is active against Gram-positive and Gram-negative bacteria. Meropenem exerts its action by penetrating bacterial cells readily and interfering with the synthesis of vital cell wall components, which leads to cell death.

Substances that inhibit the growth or reproduction of BACTERIA. (See all compounds classified as Anti-Bacterial Agents.)

Approximately 70% of the intravenously administered dose is recovered as unchanged meropenem in the urine over 12 hours, after which little further urinary excretion is detectable.|Approximately 70% of the intravenously 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 ug/mL are maintained for up to 5 hours after a 500 mg dose.|Meropenem is distributed into most body tissues and fluids, including bronchial mucosa, lung, bile, gynecologic tissue (endometrium, myometrium, ovary, cervix, fallopian tube), muscle, heart valves, skin, interstitial and peritoneal fluid, and CSF. Plasma protein binding is approximately 2%. The drug is partially metabolized to at least one microbiologically inactive metabolite. About 70% of an IV dose is eliminated in urine as unchanged drug by tubular secretion and glomerular filtration.|At the end of a 30 minute intravenous infusion of a single dose of Meropenem for injection (IV) in healthy volunteers, mean peak plasma concentrations of meropenem are approximately 23 ug/mL (range 14-26) for the 500 mg dose and 49 ug/mL (range 39-58) for the 1 g dose. A 5-minute intravenous bolus injection of Meropenem for injection (IV) in healthy volunteers results in mean peak plasma concentrations of approximately 45 ug/mL (range 18-65) for the 500 mg dose and 112 ug/mL (range 83-140) for the 1 g dose. Following intravenous doses of 500 mg, mean plasma concentrations of meropenem usually decline to approximately 1 ug/mL at 6 hours after administration. No accumulation of meropenem in plasma was observed with regimens using 500 mg administered every 8 hours or 1 g administered every 6 hours in healthy volunteers with normal renal function.

Primarily excreted unchanged. There is one metabolite which is microbiologically inactive.|There is one metabolite of meropenem that is microbiologically inactive.

Approximately 1 hour in adults and children 2 years of age and older with normal renal function. Approximately 1.5 hours in children 3 months to 2 years of age.|The plasma half-life of meropenem is approximately 1 hour in adults with normal renal function and 1.5 hours in children 3 months to 2 years of age. Plasma half-life is increased and clearance of the drug is decreased in patients with renal impairment.

The bactericidal activity of meropenem results from the inhibition of cell wall synthesis. Meropenem readily penetrates the cell wall of most Gram-positive and Gram-negative bacteria to reach penicillin-binding- protein (PBP) targets. Its strongest affinities are toward PBPs 2, 3 and 4 of Escherichia coli and Pseudomonas aeruginosa; and PBPs 1, 2 and 4 of Staphylococcus aureus.|The bactericidal activity of meropenem results from the inhibition of cell wall synthesis. Meropenem readily penetrates the cell wall of most Gram-positive and Gram-negative bacteria to reach penicillin-binding-protein (PBP) targets. Its strongest affinities are toward PBPs 2, 3 and 4 of Escherichia coli and Pseudomonas aeruginosa; and PBPs 1, 2, and 4 of Staphylococcus aureus. Bactericidal concentrations (defined as a 3 log10 reduction in cell counts within 12 to 24 hours) are typically 1-2 times the bacteriostatic concentrations of meropenem, with the exception of Listeria monocytogenes, against which lethal activity is not observed.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/CASE REPORTS/ A male patient was hospitalized as a case of pneumonia. He was diabetic, hypertensive and post Hepatitis "C". He reported skin eruption following administration of meropenem. Skin biopsy revealed acute generalized exanthematous pustulosis. ... The diagnosis was made after excluding all other possible causes. Dermatologists and clinicians must be aware of this .. unusual side effect.|/CASE REPORTS/ Vanishing bile duct syndrome is a rare and potentially life-threatening disorder in which progressive destruction and disappearance of small intrahepatic bile ducts occur, with resultant cholestasis. The mechanism by which biliary epithelial cells are damaged and intrahepatic bile ducts are lost has not been fully elucidated. However, many etiologies have been reported,and several drugs have been implicated. Meropenem is a widely used, well tolerated broad-spectrum carbapenem antibiotic indicated for the treatment of intraabdominal infections, complicated skin and skin structure infections, and pediatric bacterial meningitis. We describe what we believe is the first reported case of meropenem-induced vanishing bile duct syndrome. A 60-year-old woman was diagnosed with vanishing bile duct syndrome after being treated with meropenem for a left temporal lobe brain abscess. Three weeks after starting the drug, the patient developed mixed hepatocellular and cholestatic liver injury with jaundice and pruritus.Meropenem-induced liver injury was suspected, and the drug was discontinued. Diagnostic tests ruled out other causes of cholestasis, including infectious and immunologic conditions. A liver biopsy, performed due to persistent liver injury, demonstrated an absence of bile ducts, which, in conjunction with the patient's clinical course, was consistent with the diagnosis of vanishing bile duct syndrome. Several months after the cessation of meropenem, the patient's liver function test results improved. Use of the Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 6) between the patient's development of vanishing bile duct syndrome and meropenem therapy. A high index of suspicion is necessary to diagnose vanishing bile duct syndrome and other types of drug induced liver injury. Clinicians should consider vanishing bile duct syndrome as a potential diagnosis in patients receiving meropenem who have prolonged cholestasis, especially after other more probable causes have been excluded.|/GENOTOXICITY/ Genetic toxicity studies were performed with meropenem using the ... cultured human lymphocytes cytogenic assay ... . There was no evidence of mutagenic potential found in /this test/.

3-(5-dimethylcarbamoylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo(3.2.0)hept-2-ene-2-carboxylic acid

Table: Meropenem (Trihydrate) Preparations [Table#7976]

The present work reports a microbiological assay, applying the cylinder-plate method, for the determination of meropenem in powder for injection.

A sensitive and rapid HPLC assay for the determination of the beta-lactam antibiotics ceftazidime and meropenem in serum and bronchial secretions is described. HPLC-integrated sample preparation allows direct injection of serum samples without any pretreatment. Sputum samples need only a simple homogenisation and volume measurement but no liquefying reagents are necessary.|A simple and sensitive high-performance liquid chromatography (HPLC) method with ultraviolet (UV) detection has been developed and validated for simultaneous quantification of five beta-lactam antibiotics in human plasma: cefepim, ceftazidim, cefuroxim, meropenem and piperacillin. The plasma sample, after spiked with ceforanid as an internal standard (IS), was submitted to a solid-phase extraction (SPE) prior to HPLC analysis. A chromatographic separation was achieved on a C8 symmetry column with a mobile phase consisting of an acetonitrile and phosphate buffer (pH 7.4) mixture in a gradient mode. Detection was carried out at a wavelength between 200 and 400 nm.|A rapid, accurate and sensitive liquid chromatographic assay with on-line solid-phase extraction for determination of meropenem in serum is described. Sample was directly injected onto the extraction column for sample clean-up and extraction. Thereafter, using an on-line column-switching system the drug was quantitatively transferred and separated on a C18 analytical column. Ultraviolet absorption at 298 nm was used for detection. The assay was linear from 1 to 100 micrograms/mL. Recovery was 98.5%. Based on a 20-microliters sample volume (serum- water, 1:1, v/v), detection limit was 0.1 microgram/mL.|Concentration determination of meropenem, a carbapenem antibiotic, using a capillary electrophoresis method by direct injection of serum samples without any pretreatment is described herein. Sodium tetraborate (25 mM)-sodium hydroxide (0.1 M) containing sodium dodecyl sulfate (90 mM) is used as a run buffer (pH 10.0). Meropenem is detected at its absorption maximum at 297 nm. Migration time of meropenem is approximately 7.2 min, and the detection limit of the assay is 2.0 mg/L at a signal-to-noise ratio of 3.0. The relative standard deviations of intra- and interassay accuracies are 3.43-8.87% and 4.28-8.54%, respectively, at a nominal concentration of 6.3-100.0 mg/L, and their recovery rates are 94-111% and 92-105%, respectively.

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