Carmepem

Meropenem.

Each vial contains: Meropenem trihydrate and dried sodium carbonate 1.208 g (1 g as Meropenem).

Pharmacology: Pharmacokinetics: Plasma concentrations: At the end of a 30- minute intravenous infusion of a single dose of Meropenem Powder for Injection (IV) (Intravenous) in healthy volunteers, mean peak plasma concentrations of Meropenem are approximately 23 mcg/mL (range 14 to 26) for the 500 mg dose and 49 mcg/mL (range 39 to 58) for the 1 gram dose.
A 5-minute intravenous bolus injection of Meropenem Powder for injection I.V. in healthy volunteers results in mean peak plasma concentrations of approximately 45 mcg/mL (Range 18 to 65) for the 500 mg dose and 112 mcg/mL (range 83 to 140) for the 1 gram dose.
Following intravenous doses of 500 mg, mean plasma concentrations of Meropenem usually decline to approximately 1 mcg/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 gram administered every 6 hours in healthy volunteers with normal renal function.
Distribution: The plasma protein binding of Meropenem is approximately 2%.
Meropenem penetrates well into most body fluids and tissues including cerebrospinal fluid, achieving concentrations matching or exceeding those required to inhibit most susceptible bacteria. After a single intravenous dose of Meropenem Powder for injection (IV), the highest mean concentrations of Meropenem were found in tissues and fluids at 1 hour (0.5 to 1.5 hours) after the start of infusion, except where Indicated in the tissues and fluids listed in the table as follows. (See Table 1.)

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Metabolism: There is one metabolite of Meropenem that ls microbiologically inactive.
Excretion: In subjects with normal renal function, the elimination half-life of Meropenem is approximately 1 hour. Meropenem is primarily excreted unchanged by the kidneys. Approximately 70% (50% to 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. Urinary concentrations of Meropenem in excess of 10 mcg/mL are maintained for up to 5 hours after a 500 mg dose.
Microbiology: Mechanism of Action: 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 log 10 reduction in cell counts within 12 hours to 24 hours) are typically 1 to 2 times the bacteriostatic concentrations of Meropenem, with the exception of Listeria monocytogenes, against which lethal activity is not observed.
Meropenem has significant stability to hydrolysis by β-lactamases, both penicillinases and cephalosporinases produced by Gram-positive and Gram-negative bacteria.
Meropenem should not be used to treat methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-resistant Staphylococcus epidermidis (MRSE).
Mechanism of Resistance: There are several mechanisms of resistance to carbapenems: 1. decreased permeability of the outer membrane of Gram-negative bacteria (due to diminished production of porins) causing reduced bacterial uptake; 2. reduced affinity of the target PBPs; 3. increased expression of efflux pump components, and; 4. production of antibacterial drug-destroying enzymes (carbapenemases, metallo-β-lactamases). Localized clusters of infections due to carbapenem-resistant bacteria have been reported in some regions.
Cross-Resistance: Cross-resistance is sometimes observed with isolates resistant to other carbapenems. Interactions with Other Antibacterial Drugs. In vitro tests show Meropenem to act synergistically with aminoglycoside antibacterials against some isolates of Pseudomonas aeruginosa.
Spectrum of Activity: Meropenem has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical Infections as described (see Indications).
Gram-positive bacteria: Enterococcus faecalis (vancomycin-susceptible isolates only)
Staphylococcus aureus (methicillin-susceptible isolates only)
Streptococcus agalactiae
Streptococcus pneumoniae (penicillin-susceptible isolates only)
Streptococcus pyogenes
Viridans group streptococci
Gram-negative bacteria: Escherichia coli; Neisseria meningitidis; Anaerobic bacteria; Peptostreptococcus species; Haemophtlus influenzae; Pseudomonas aeruginosa; Bacteroides fragilis; Klebsiella pneumoniae; Proteus mirabilis; Bacteroides thetaiotaomicron.
The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following bacteria have exhibited in vitro minimum inhibitory concentrations (MICs) less than or equal to the susceptible breakpoints for Meropenem. However, the safety and effectiveness of Meropenem in treating clinical infections due to these bacteria have not been established in adequate and well-controlled trials.
Gram-positive bacteria: Staphylococcus epidermidis (methicillin-susceptible isolates only).
Gram-negative bacteria: Aeromonas hydrophila; Citrobacter freundii; Klebsiella oxytoca; Pasteurella multocida; Anaerobic bacteria; Bacteroides uniformis; Campylobaeter jejuni; Enterobacter cloacae; Moraxella catarrhalis; Proteus vulgaris; Bacteroides distasonis; Bacteroides ureolyticus; Citrobacter koseri (formerly diversus); Hafnia alvei; Morganella morganii; Serratia marcescens; Bacteroides ovatus; Baeteroides vulgatus.

CARMEPEM (Meropenem) Powder for injection (IV) is a penem antibacterial indicated as single agent therapy for the treatment of: Complicated skin and skin structure infections (adult patients and pediatric patients 3 months of age and older only).
Complicated intra-abdominal infections (adult and pediatric patients).
Bacterial meningitis (pediatric patients 3 months of age and older only).

500 mg every 8 hours by intravenous infusion over 15 minutes to 30 minutes for skin and skin structure infections for adult patients. When treating infections caused by Pseudomonas aeruginosa, a dose of 1 gram every 8 hours is recommended.
1 gram every 8 hours by intravenous infusion over 15 minutes to 30 minutes for intra-abdominal infections for adult patients.
1 gram every 8 hours by intravenous bolus injection (5 mL to 20 mL) over 3 minutes to 5 minutes for adult patients.
Dosage should be reduced in adult patients with renal impairment. (See Table 2.)

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Pediatric patients 3 months of age and older: (See Table 3.)

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Pediatric patients less than 3 months of age: (See Table 4.)

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Preparation of Solution: For Intravenous Bolus Administration: Constitute injection vials (500 mg and 1 gram) with sterile Water for injection. See table below. Shake to dissolve and let stand until clear. (See Table 5.)

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For Infusion: Infusion vials (500 mg and 1 gram) may be directly constituted with a compatible infusion fluid. Alternatively, an injection vial may be constituted, then the resulting solution added to an intravenous container and further diluted with an appropriate infusion fluid (see Dosage and Administration as follows.)
WARNING: Do not use flexible container in series connections.
Compatibility: Compatibility of Meropenem with other drugs has not been established. Meropenem should not be mixed with or physically added to solutions containing other drugs.
Stability and Storage: Freshly prepared solutions of Meropenem should be used. However, constituted solutions of Meropenem maintain satisfactory potency under the conditions described as follows. Solutions of intravenous Meropenem should not be frozen.
Intravenous Bolus Administration: Meropenem Powder for injection (IV) vials constituted with sterile Water for injection for bolus administration (up to 50 mg/mL of Meropenem) may be stored for up to 3 hours at up to 25°C (77°F) or for 13 hours at up to 5°C (41°F).
Intravenous Infusion Administration: Solutions prepared for infusion (Meropenem Powder for lnjection (IV) concentrations ranging from 1 mg/mL to 20 mg/mL) constituted with Sodium Chloride injection 0.9% may be stored for 1 hour at up to 25°C (77°F) or 15 hours at up to 5°C (41°F).
Solutions prepared for infusion (Meropenem Powder for lnjection (IV)) concentrations ranging from 1 mg/mL to 20 mg/mL) constituted with Dextrose injection 5% should be used immediately.
NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

In mice and rats, large intravenous doses of Meropenem Powder for injection (IV) (2200 mg/kg to 4000 mg/kg) have been associated with ataxia, dyspnea, convulsions, and mortalities. Intentional overdosing of Meropenem Powder for injection (IV) 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 grams given intravenously every 8 hours. At this dosage, no adverse pharmacological effects or increased safety risks have been observed.
Limited postmarketing experience indicates that If adverse events occur following overdosage, they are consistent with the adverse event profile described in the Adverse Reactions section and are generally mild in severity and resolve on withdrawal or dose reduction. Consider symptomatic treatments. In individuals with normal renal function, rapid 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.

Meropenem Powder 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 β-lactams.

Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with β-lactams. 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 hypersensitivity reactions when treated with another β-lactam. Before initiating therapy with Meropenem Powder for injection (IV), it is important to inquire about previous hypersensitivity reaction, to penicillins, cephalosporins, other β-lactams, and other allergens. If an allergic reaction to Meropenem for injection I.V. occurs, discontinue the drug immediately. Serious anaphylactic reactions require immediate emergency treatment with epinephrine, oxygen, intravenous steroids, and airway management, including intubation. Other therapy may also be administered as indicated.
Seizure Potential: Seizures and other adverse Central Nervous System (CNS) experiences have been reported during treatment with Meropenem Powder for injection (IV). These experiences have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) or with bacterial meningitis and/or compromised renal function (see Adverse Reactions and Interactions).
During clinical investigations, 2904 immunocompetent adult patients were treated for non-CNS infections with the overall seizure rate being 0.7% (based on 20 patients with this adverse event). Meropenem-treated patients with seizures had pre-existing contributing factors. Among these are included prior history of seizures or CNS abnormality and concomitant medications with seizure potential. Dosage adjustment is recommended in patients with advanced age and/or reduced renal function (see Dosage & Administration).
Close adherence to the recommended dosage regimens is urged, especially in patients with known factors that predispose to convulsive activity. Continue anticonvulsant therapy in patients with known seizure disorders. If focal tremors, myoclonus, or seizures occur, evaluate neurologically, placed on anticonvulsant therapy if not already instituted, and the dosage of Meropenem Powder for injection (IV) re-examined to determine whether it should be decreased or the antibacterial drug discontinued.
Interaction with Valproic Acid: 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. Increasing the dose of valproic acid or divalproex sodium may not be sufficient to overcome this interaction. The concomitant use of Meropenem and valproic acid or divalproex sodium is generally not recommended. Antibacterials other than carbapenems should be considered to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium. If administration of Meropenem Powder for injection (IV) is necessary, supplemental anticonvulsant therapy should be considered (see Interactions).
Clostridium difficile-associated Diarrhea: Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Meropenem Powder for injection (IV), and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing isolates of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Development of Drug-Resistant Bacteria: Prescribing Meropenem Powder for injection (IV) in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
Overgrowth of Non-susceptible Organisms: as with other broad-spectrum antibacterial drugs, prolonged use of Meropenem may result in overgrowth of non-susceptible organisms. Repeated evaluation of the patient is essential. If superinfection does occur during therapy, appropriate measures should be taken.
Laboratory Tests: While Meropenem Powder for injection (IV) possesses the characteristic low toxicity of the beta-lactam group of antibacterial drugs, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy.
Patients with Renal Impairment: In patients with renal impairment, thrombocytopenia has been observed but no clinical bleeding reported (see Dosage & Administration, Adverse Reactions, Pharmacology under Actions).
Dialysis: There is Inadequate information regarding the use of Meropenem Powder for injection (IV) in patients on hemodialysis or peritoneal dialysis.
Potential for Neuromotor Impairment: Patients receiving Meropenem Powder for injection (IV) on an outpatient basis may develop adverse events such as seizures, headaches and/or paresthesias that could interfere with mental alertness and/or cause motor Impairment. Until it is reasonably well established that Meropenem Powder for injection (IV) is well tolerated, patients should not operate machinery or motorized vehicles (see Adverse Reactions).

Pregnancy: Pregnancy Category B. Reproductive studies have been performed with Meropenem in rats at doses of up to 1000 mg/kg/day, and cynomolgus monkeys at doses of up to 360 mg/kg/day (on the basis of area under the curve (AUC) comparisons, approximately 1.8 times and 3.7 times, respectively, to the human exposure at the usual dose of 1 gram 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 250 mg/kg/day (on the basis of AUC comparisons, 0.4 times the human exposure at a dose of 1 gram every 8 hours) and above in rats. There are, however, 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.
Nursing Mothers: Meropenem has been reported to be excreted in human milk. Caution should be exercised when Meropenem Powder for injection (IV) is administered to a nursing woman.

Hypersensitivity Reactions (see Precautions); Seizure Potential (see Precautions); Interaction with Valproic Acid (see Precautions); Clostridium difficile - associated Diarrhea (see Precautions); Development of Drug-Resistant Bacteria (see Precautions); Overgrowth of Non-susceptible Organisms (see Precautions); Laboratory Tests (see Precautions); Patients with Renal Impairment (see Precautions); Dialysis (see Precautions). Potential for Neuromotor Impairment (see Precautions).

Probenecid: Probenecid competes with Meropenem for active tubular secretion, resulting in increased plasma concentrations of Meropenem. Co-administration of probenecid with Meropenem is not recommended.
Valproic Acid: 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 Powder for injection (IV) is necessary, then supplemental anti-convulsant therapy should be considered (see Precautions).

The preparation should be used immediately after reconstitution.
0.9% NaCl - store within 12 hours at temperatures between 2-8°C.
5% Glucose - store within 24 hours at temperatures between 2-8°C.
It Is colorless or yellowish clear when this drug is dissolved. Intensity of color does not impact in drug effect.
For intravenous use only.

Store at temperatures not exceeding 30°C. Do not freeze.
Shelf-life: 36 months from manufacturing date.

Other Beta-Lactams

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

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