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MERREM
Zeneca
Meropenem
Antibiotic
 
Action And Clinical Pharmacology: Meropenem is a broad spectrum, b-lactamase-resistant, carbapenem antibiotic for parenteral administration.

The bactericidal activity of meropenem results from the inhibition of bacterial cell wall synthesis. Meropenem readily penetrates through the cell wall of most gram-positive and gram-negative bacteria to reach penicillin binding protein (PBP) targets. Its greatest affinity is for PBP 2 of E. coli, PBP 2 and 3 of P. aeruginosa and 1, 2 and 4 of S. aureus.

Meropenem is stable in the presence of all serine b-lactamases (both penicillinases and cephalosporinases) produced by gram-positive and gram-negative bacteria.

Pharmacokinetics: At the end of a 30-minute i.v. infusion of a single dose of meropenem in healthy, male volunteers, mean peak plasma concentrations are approximately 23 g/mL for the 500 mg dose, 49 g/mL for the 1 g dose and 115 g/mL for the 2 g dose.

I.V. bolus injections of a 1 g dose of meropenem over 2 minutes, 3 minutes and 5 minutes were compared in a 3-way crossover trial in healthy male volunteers. This resulted in peak plasma levels of 110, 91 and 94 g/mL, respectively.

A 5-minute i.v. bolus injection of meropenem in healthy, male volunteers results in mean peak plasma levels of approximately 52 g/mL for the 500 mg dose and 112 g/mL for the 1 g dose.

At doses of 500 mg, mean plasma levels of meropenem decline to 1 g/mL or less, 6 hours after administration.

In subjects with normal renal function, the elimination half-life of meropenem is approximately 1 hour. Approximately 70% of the administered dose is recovered unchanged in the urine over 12 hours, after which little further urinary excretion is detectable. Urinary concentrations of meropenem in excess of 10 g/mL are maintained for at least 5 hours at the 500 mg dose. No clinically important accumulation of meropenem in plasma or urine was observed with regimens using 500 mg administered every 8 hours or 1 g administered every 6 hours in volunteers with normal renal function. Plasma protein binding of meropenem is approximately 2%.

There is one metabolite which is microbiologically inactive. In healthy subjects, the AUC for this metabolite was approximately 10% of the AUC for meropenem.

Meropenem penetrates well into most body fluids and tissues. However, it does not penetrate readily into cerebrospinal fluid or aqueous humor in the absence of inflammation at the sites. In children and adults with bacterial meningitis, meropenem concentrations in the cerebrospinal fluid, after i.v. administration of recommended doses, are in excess of those required to inhibit susceptible bacteria.

The pharmacokinetics of meropenem in children over age 2 are essentially similar to those in adults. The elimination half-life for meropenem was approximately 1.5 hours in children of age 3 months to 2 years. The pharmacokinetics for children are linear for doses of 10, 20 and 40 mg/kg and the peak plasma concentrations and AUC values are similar to those seen in healthy adult volunteers after 500 mg, 1 g and 2 g doses, respectively.

Pharmacokinetic studies of meropenem in patients with renal insufficiency have shown that the plasma clearance of meropenem correlates with creatinine clearance. Dosage adjustments are necessary in subjects with renal impairment (see Dosage). A pharmacokinetic study with meropenem in elderly patients with renal insufficiency has shown that a reduction in plasma clearance of meropenem correlates with age-associated reduction in creatinine clearance.

A pharmacokinetic study of meropenem in patients with hepatic impairment has shown no effects of liver disease on the pharmacokinetics of meropenem.

Indications And Clinical Uses: For treatment of the following infections when caused by susceptible strains of the designated microorganisms: Lower Respiratory Tract: Community-acquired pneumonia caused by S. aureus (b-lactamase-producing and non-b-lactamase-producing), S. pneumoniae, E. coli and H. influenzae (b-lactamase-producing and non-b-lactamase-producing).

Nosocomial pneumonia caused by S. aureus (non-b-lactamase-producing), E. coli, H. influenzae (non-b-lactamase-producing), K. pneumoniae and P. aeruginosa.

Urinary Tract: Complicated urinary tract infections caused by E. cloacae, E. coli, K. pneumoniae, P. aeruginosa and S. marcescens.

Intra-abdominal: Complicated intra-abdominal infections caused by S. milleri, S. mitior, S. sanguis, C. freundii, E. cloacae, E. coli, K. oxytoca, K. pneumoniae, M. morganii, P. aeruginosa, B. distasonis, B. fragilis, B. ovatus, B. thetaiotaomicron, B. uniformis, B. vulgatus, C. perfringens, Clostridium species, E. lentum, Fusobacterium species and Peptostreptococcus species.

Clinical trials of meropenem in patients with complicated intra-abdominal infections have demonstrated that the efficacy against E. faecalis is 71%.

Gynecologic: Gynecologic infections caused by E. faecalis, S. aureus (b-lactamase-producing and non-b-lactamase producing), S. epidermidis (non-b-lactamase-producing), E. coli, Fusobacterium species, P. bivia, P. disiens, P. intermedia and Peptostreptococcus species.

Pelvic inflammatory disease caused by S. epidermidis (non-b-lactamase-producing), S. agalactiae, E. coli, N. gonorrhoeae (non-b-lactamase-producing) and P. bivia.

Note: Meropenem has no activity against C. trachomatis. Additional antimicrobial coverage is required if this pathogen is expected.

Skin and Skin Structure: Uncomplicated skin and skin structure infections caused by S. aureus (b-lactamase-producing and non-b-lactamase-producing), S. agalactiae, S. pyogenes and E. coli.

Bacterial Meningitis: Bacterial meningitis caused by S. pneumoniae, H. influenzae (b-lactamase-producing and non-b-lactamase-producing) and N. meningitidis.

Note: There is limited adult efficacy data for meropenem in the treatment of bacterial meningitis. Support for the adult meningitis indication is largely provided by pediatric data.

Bacterial Septicemia: Bacterial septicemia caused by E. coli.

Therapy with meropenem may be initiated on the basis of clinical judgment before results of sensitivity testing are available. Continuation of therapy should be re-evaluated on the basis of bacteriological findings and on the patient's clinical condition. Regular sensitivity testing is recommended when treating P. aeruginosa infections.

Contra-Indications: Patients with known hypersensitivity to any component of this product or in patients who have demonstrated anaphylactic reactions to b-lactam antibiotics. tag_WarningWarnings

Manufacturers' Warnings In Clinical States: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with b-lactam antibiotics. These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens.

There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with another b-lactam antibiotic. Before initiating therapy with meropenem, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, other b-lactam antibiotics, and other allergens. If an allergic reaction to meropenem occurs, discontinue the drug immediately. Anaphylactic reactions require immediate treatment with epinephrine. Oxygen, i.v. steroids, antihistamines and airway management, including intubation, may be required.

Pseudomembranous colitis has been reported with many antibiotics, including meropenem; therefore, it is important to consider this diagnosis in patients who develop diarrhea in association with antibiotic use. This colitis may range in severity from mild to life threatening.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of Clostridia. Studies indicated that a toxin produced by C. difficile is one primary cause of antibiotic-associated colitis.

After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug effective against C. difficile.

Meropenem should not be used to treat infections caused by methicillin resistant staphylococci.

Precautions: General: As with other broad-spectrum antibiotics, prolonged use of meropenem may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the patient is essential. If superinfection does occur during therapy, appropriate measures should be taken.

Meropenem, like all b-lactam antibiotics, has the potential to cause seizures. Diminished renal function and CNS lesions may increase the risk of seizures. When meropenem is indicated in patients with these risk factors, caution is advised.

Children: The safety and effectiveness of meropenem have been established only for those infants and children 3 months of age and older.

The use of meropenem in pediatric patients with bacterial meningitis is supported by evidence from adequate and well controlled studies in the pediatric population. Use of meropenem in pediatric patients for all other indications, as listed in the Indications section, is supported by evidence from adequate and well controlled studies in adults with additional data from pediatric pharmacokinetic studies and controlled clinical trials in pediatric patients (see Dosage, Children).

Note: Inadequate data are available to support the pediatric indications for nosocomial pneumonia and for septicemia.

Pregnancy: There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Reproduction studies have been performed in rats and Cynomolgus monkeys at doses up to 1 000 mg/kg/day (approximately 16 times the usual human dose of 1 g every 8 hours). These studies revealed no evidence of impaired fertility or harm to the fetus due to meropenem although there were slight changes in fetal body weight at doses of 240 mg/kg/day and above in rats.

Lactation: It is not known whether meropenem is excreted in human milk. Therefore, caution should be exercised when considering the administration of meropenem to a nursing woman.

Liver Disease: Patients with pre-existing liver disorders should have their liver function monitored during treatment with meropenem.

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. The coadministration of probenecid with meropenem is neither required nor recommended.

Other than probenecid, no specific drug interaction studies were conducted.

Adverse Reactions: Local Adverse Reactions: Meropenem is generally well tolerated. The following adverse reaction frequencies were derived from all clinical trials in 2 676 patients treated with meropenem administered i.v. and in 481 patients treated with an i.m. injection formulation of meropenem. Local adverse clinical reactions that were reported as possibly, probably or definitely related to therapy with meropenem were: inflammation at the injection site 2.4%, phlebitis/thrombophlebitis 0.8%, injection site reaction 0.7%, pain at the injection site 0.2% and edema at the injection site 0.1%.

Systemic Adverse Reactions: Systemic adverse clinical reactions that were reported as possibly, probably or definitely related to meropenem and occurring in greater than 0.2% of the patients were: diarrhea (2.6%), nausea/vomiting (1.2%), rash (1.2%), pruritus (0.6%), headache (0.4%), urticaria (0.3%), vaginal moniliasis (0.4%), oral moniliasis (0.2%) and fever (0.2%).

Additional adverse systemic clinical reactions reported as possibly, probably or definitely related to meropenem and occurring in less than 0.2% of the patients are listed below within each body system in order of decreasing frequency.

Body as a Whole: abdominal pain, moniliasis, chills, infection, pain.

Nervous System: agitation, convulsions, dizziness, hallucinations, paresthesias, neuropathy.

Skin and Appendages: sweating.

Urogenital System: vaginitis.

Special Senses: taste perversion.

Digestive System: constipation.

Metabolic/Nutritional: peripheral edema.

Adverse Laboratory Changes: Adverse laboratory changes that were reported as possibly, probably or definitely related to meropenem occurring in greater than 0.2% of the patients were as follows: Hepatic: increased ALT, AST, alkaline phosphatase, LDH and bilirubin.

Hematologic: increased platelets, increased eosinophils, abnormal prothrombin time, abnormal partial thromboplastin time, decreased platelets, positive direct or indirect Coombs' test and decreased WBC.

Renal: increased creatinine and increased BUN.

Children: Drug-related diarrhea (5%) and increases in platelets (7%) appear to occur more frequently in pediatric patients than in adults treated with meropenem.

Symptoms And Treatment Of Overdose: Symptoms: Intentional overdosing of meropenem is unlikely, although accidental overdosing might occur if large doses are given to patients with reduced renal function. The largest dose of meropenem administered in clinical trials has been 2 g given i.v. every 8 hours to adult patients with normal renal function and 40 mg/kg every 8 hours to children with normal renal function. At these dosages, no adverse pharmacological effects were observed. tag_Treatment

Treatment: No specific information is available for the treatment of meropenem overdosage. In the event of an overdose, meropenem should be discontinued and general supportive treatment given until renal elimination takes place. Meropenem and its metabolite are readily dialyzable and effectively removed by hemodialysis; however, no information is available on the use of hemodialysis to treat overdosage.

The i.v. LD50 of meropenem in mice and rats is more than 2 500 mg/kg and is approximately 2 000 mg/kg in dogs.

Dosage And Administration: Adults: The usual dose is 500 mg to 1 g by i.v. infusion every 8 hours, depending on type and severity of infection, the known or suspected susceptibility of the pathogens and the condition of the patient (see Table I). Doses up to 2 g every 8 hours have been used. Meropenem should be given by i.v. infusion over approximately 15 to 30 minutes or as an i.v. bolus injection (5 to 20 mL) over approximately 5 minutes.

CPS:TABLE_c6790e__._10_t1Merrem

Recommended Dose - Adults Type of Infection, Dose, Dosage Interval

Complicated urinary tract, 500 mg, every 8 hours

Uncomplicated skin and skin structure, 500 mg, every 8 hours

Gynecologic and pelvic inflammatory disease, 500 mg, every 8 hours Lower respiratory Community-acquired pneumonia, 500 mg, every 8 hours

Nosocomial pneumonia, 1 g, every 8 hours

Complicated intra-abdominal, 1 g, every 8 hours

Meningitis, 2 g, every 8 hours

Septicemia, 1 g, every 8 hours

Impaired Renal Function: Dosage should be reduced in patients with creatinine clearance less than 51 mL/min

CPS:TABLE_c6790e__._10_t2Merrem

Dosage in Impaired Renal Function Creatinine Clearance (mL/min) , Dose (dependent on type of infection) , Dosing Interval

26-50 , recommended dose (500 mg to 2 000 mg) , every 12 hours

10-25 , one-half recommended dose , every 12 hours

<10 , one-half recommended dose , every 24 hours

Meropenem is removed by hemodialysis; if continued treatment with meropenem is necessary, the dose, based on the infection type and severity, should be administered at the completion of the hemodialysis procedure to reinstitute effective treatment.

There are no data on appropriate doses in patients requiring dialysis.

Adults with Hepatic Insufficiency: No dosage adjustment is necessary in patients with hepatic dysfunction as long as renal function is normal.

Geriatrics: Dosage adjustment is recommended for the elderly with an estimated or measured creatinine clearance value below 50 mL/min (see Impaired Renal Function).

Children: For infants and children over 3 months of age and weighing up to 50 kg, the recommended dose of meropenem is 10 to 40 mg/kg every 8 hours, depending on type and severity of infection, the known or suspected susceptibility of the pathogens and the condition of the patient (see Table III). Children weighing over 50 kg require the adult dosage. Meropenem should be given as an i.v. infusion over approximately 15 to 30 minutes or as an i.v. bolus injection (5 to 20 mL) over approximately 5 minutes.

There are no data on appropriate doses for children with renal impairment.

Parenteral Products: Compatibility of meropenem with other drugs has not been established. Meropenem should not be mixed with or physically added to solutions containing other drugs.

Freshly prepared solutions of meropenem should be used whenever possible. Solutions of meropenem should not be frozen.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

I.V. Bolus Administration: Reconstitute injection vials (500 mg/20 mL and 1 g/30 mL) with Sterile Water for Injection (see Table IV). Shake to dissolve and let stand until clear.

Meropenem injection vials reconstituted with Sterile Water for Injection for bolus administration (up to 50 mg/mL) may be stored for up to 2 hours at controlled room temperature 15 to 25C or for up to 12 hours at 4C.

Infusion: Injection vials may be reconstituted, then the resulting solution added to an i.v. container and further diluted with an appropriate infusion fluid (see Table V).

Stability in Plastic I.V. Bags: Solutions prepared for infusion (meropenem concentrations ranging from 1 to 20 mg/mL) may be stored in plastic i.v. bags with diluents as shown in Table V. Diluted i.v. infusion solutions should be inspected visually for discoloration, haziness, particulate matter and leakage prior to administration, whenever solution and container permit. Discard unused portion.

Stability in Plastic Syringes, Tubing and I.V. Infusion Sets: Solutions of meropenem (concentrations ranging from 1 to 20 mg/mL) in Water for Injection or Sodium Chloride 0.9% Injection (for up to 4 hours) or in Dextrose 5% Injection (for up to 2 hours) at controlled room temperatures 15 to 25C are stable in plastic syringes, plastic tubing, drip chambers, and volume control devices of common i.v. infusion sets.

Availability And Storage: Vials: 500 mg: Each vial of dry powder contains: meropenem trihydrate equivalent to meropenem anhydrous 500 mg and sodium carbonate equivalent to sodium 45.1 mg. Vials of 20 mL.

1 g: Each vial of dry powder contains: meropenem trihydrate equivalent to meropenem anhydrous 1 g and sodium carbonate equivalent to sodium 90.2 mg. Vials of 30 mL.

Store between 15 and 30C.