Merozan

Meropenem trihydrate.

Each vial of Meropenem (Merozan) 500 mg contains Meropenem trihydrate 570 mg, EP equivalent to Meropenem anhydrous 500 mg.
Each vial of Meropenem (Merozan) 1 g contains Meropenem trihydrate 1.14 g, EP equivalent to Meropenem anhydrous 1 g.
Excipients/Inactive Ingredients: Sodium carbonate anhydrous.

ATC code: J01DH02.
Pharmacology: Pharmacodynamics: Meropenem is a carbapenem antibiotic for parenteral use, that is stable to human dehydropeptidase-1 (DHP-1). Meropenem exerts its bactericidal action by interfering with vital bacterial cell wall synthesis. The ease with which it penetrates bacterial cell walls, its high level of stability to all serine beta-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 MBC (minimum bactericidal concentration) to MIC (minimum inhibitory concentration) ratios are 2 or less. 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 on Gram-positive and Gram-negative bacteria.
A single set of meropenem susceptibility criteria are recommended based on pharmacokinetics and correlation of clinical and microbiological outcomes with zone diameter and minimum inhibitory concentrations (MIC) of the infecting organisms. (See Table 1.)

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The in vitro antibacterial spectrum of meropenem includes the majority of clinically significant Gram-positive and Gram-negative, aerobic and anaerobic strains of bacteria, as shown as follows: Gram-positive aerobes: Bacillus spp., Corynebacterium diphtheriae, Enterococcus faecalis, Enterococcus liquifaciens, Enterococcus avium, Erysipelothix rhysiopathiae, Listeria monocytogenes, Lactobacillus spp., Nocardia asteroides, Staphylococcus aureus (penicillinase negative and positive), Staphylococci-coagulase-negative; including Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus capitis, Staphylococcus cohnii, Staphylococcus xylosus, Staphylococcus warneri, Staphylococcus hominis, Staphylococcus simulans, Staphylococcus intermedius, Staphylococcus sciuri, Staphylococcus lugdunensis, Streptococcus pneumoniae (penicillin susceptible and resistant), Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus equi, Streptococcus bovis, Streptococcus mitis, Streptococcus mitior, Streptococcus milleri, Streptococcus sanguis, Streptococcus viridans, Streptococcus salivarius, Streptococcus morbillorum, Streptococcus cremoris, Streptococcus Group G, Streptococcus Group F, Rhodococcus equi.
Gram-negative aerobes: Achromobacter xylosoxidans, Acinetobacter anitratus, Acinetobacter lwoffii, Acinetobacter baumannii, Acinetobacter junii, Acinetobacter haemolyticus, Aeromonas hydrophila, Aeromonas sorbria, Aeromonas caviae, Alcaligenes faecalis, Bordatella bronchiseptica, Brucella melitensis, Campylobacter coli, Campylobacter jejuni, Citrobacter freundii, Citrobacter diversus, Citrobacter koseri, Citrobacter amalonaticus, Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter cloacae, Enterobacter sakazakii, Escherichia coli, Escherichia hermannii, Gardnerella vaginalis, Haemophilus influenzae (including beta-lactamase positive and ampicillin resistant strains), Haemophilus parainfluenzae, Haemophilus ducreyi, Helicobacter pylori, Neisseria meningitidis, Neisseria gonorrhoeae (including beta-lactamase positive, penicillin resistant and spectinomycin resistant strains), Hafnia alvei, Klebsiella pneumoniae, Klebsiella aerogenes, Klebsiella ozaenae, Klebsiella oxytoca, Moraxella (Branhamella) catarrhalis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Proteus penneri, Providencia rettgeri, Providencia stuartii, Providencia alcalifaciens, Pasteurella multocida, Plesiomonas shigelloides, Pseudomonas aeruginosa, Pseudomonas putida, Pseudomonas alcaligenes, Pseudomonas cepacia, Pseudomonas fluorescens, Pseudomonas stutzeri, Pseudomonas pickettii, Pseudomonas pseudomallei, Pseudomonas acidovorans, Salmonella spp. including Salmonella enteritidis/typhi, Serratia marcescens, Serratia liquefaciens, Serratia rubidaea, Shigella sonnei, Shigella flexneri, Shigella boydii, Shigella dysenteriae, Vibrio cholerae, Vibrio parahaemolyticus, Vibrio vulnificus, Yersinia enterocolitica.
Anaerobic bacteria: Actinomyces odontolyticus, Actinomyces meyeri, Actinomyces israelii, Bacteroides-Prevotella-Porphyromanas spp., Bacteroides fragilis, Bacteroides vulgatus, Bacteroides variabilis, Bacteroides pneumosintes, Bacteroides coagulans, Bacteroides uniformis, Bacteroides distasonis, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides eggerthii, Bacteroides capsillosis, Bacteroides gracilis, Bacteroides levii, Bacteroides caccae, Bacteroides ureolyticus, Prevotella buccalis, Prevotella melaninogenica, Prevotella intermedia, Prevotella bivia, Prevotella corporis, Prevotella splanchnicus, Prevotella oralis, Prevotella disiens, Prevotella rumenicola, Prevotella oris, Prevotella buccae, Prevotella denticola, Porphyromonas asaccharolyticus, Porphyromonas gingivalis, Bifidobacterium spp., Bilophila wadsworthia, Clostridium perfringens, Clostridium bifermentans, Clostridium ramosum, Clostridium sporogenes, Clostridium cadaveris, Clostridium difficile, Clostridium sordellii, Clostridium butyricum, Clostridium clostridiiformis, Clostridium innocuum, Clostridium subterminale, Clostridium tertium, Eubacterium lentum, Eubacterium aerofaciens, Fusobacterium mortiferum, Fusobacterium necrophorum, Fusobacterium nucleatum, Fusobacterium varium, Mobiluncus curtisii, Mobiluncus mulieris, Peptostreptococcus anaerodius, Peptostreptococcus micros, Peptostreptococcus saccharolyticus, Peptococcus saccharolyticus, Peptostreptococcus saccharolyticus, Peptostreptococcus magnus, Peptostreptococcus prevotii, Propionibacterium acnes, Propionibacterium avidium, Propionibacterium granulosum, Veillonella parvula, Wolinella recta. Stenotrophomonas (Xanthomonas) maltophilia, Enterococcus faecium and methicillin-resistant staphylococci have been found to be resistant to meropenem.
Pharmacokinetics: A 30-minute intravenous infusion of a single dose of meropenem in healthy volunteers resulted in peak plasma levels of approximately 11 μg/ml for the 250 mg dose, 23 μg/ml for the 500 mg dose and 49 μg/ml for the 1g dose. However, there is no absolute pharmacokinetic proportionality with the administered dose both as regards Cmax and AUC. Furthermore, a reduction in plasma clearance from 287 to 205 ml/min for the range of dosage 250 mg to 2 g has been observed.
A 5-minute intravenous bolus injection in healthy volunteers resulted in peak plasma levels of approximately 52 μg/ml for the 500 mg dose and 112 μg/ml for the 1g dose. Intravenous infusions of 1 g over 2 minutes, 3 minutes and 5 minutes were compared in a three-way crossover trial. These durations of infusion resulted in peak plasma levels of 110, 91 and 94 microgram/ml, respectively. After an IV dose of 500 mg, plasma levels of meropenem decline to values of 1 microgram/ml or less, 6 hours after administration. When multiple doses are administered at 8 hourly intervals to subjects with normal renal function, accumulation of meropenem does not occur.
In patients with normal renal function, meropenem's elimination half-life is approximately 1 hour. Plasma protein binding of meropenem is approximately 2%. Approximately 70% of the 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 μg/ml are maintained for up to 5 hours after the administration of a 500 mg dose. No 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.
The only metabolite of meropenem is microbiologically inactive. Meropenem penetrates well into most body fluids and tissues including cerebrospinal fluid of patients with bacterial meningitis, achieving concentrations in excess of those required to inhibit most bacteria. Studies in children have shown that the pharmacokinetics of meropenem in children are similar to those in adults. The elimination half-life for meropenem was approximately 1.5 to 2.3 hours in children under the age of 2 years and the pharmacokinetics are linear over the dose range of 10 to 40 mg/kg.
Pharmacokinetic studies in patients with renal insufficiency have shown the plasma clearance of meropenem correlates with creatinine clearance. Dosage adjustments are necessary in patients with renal impairment. Pharmacokinetic studies in the elderly have shown a reduction in plasma clearance of meropenem which correlated with age-associated reduction in creatinine clearance. Pharmacokinetic studies in patients with liver disease have shown no effects of liver disease on the pharmacokinetics of meropenem.
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). Effects on the CNS, convulsions in rats and vomiting in dogs, were seen only at high doses >2000 mg/kg). For an IV dose the LD50 in rodents is greater than 2000 mg/kg. In repeat dose studies (up to 6 months) 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 rat 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 intravenous formulation was well tolerated in animal studies. The sole metabolite of meropenem had a similar profile of toxicity in animal studies.

Meropenem (Merozan) is indicated for treatment, in adults and children, of the following infections caused by single or multiple bacteria sensitive to meropenem.
Nosocomial pneumonias, pneumonias in immunosuppressed patients, pneumonias not responding to other antibacterial treatments, due to bacteria susceptible to meropenem according to the susceptibility test; Urinary tract infections (complicated and non-complicated); Intra-abdominal infections; Gynaecological infections, such as endometritis and pelvic inflammatory disease; Infections of the skin and soft tissues; Meningitis; Septicaemia; Empiric treatment, for presumed infections in adult patients with febrile neutropenia.
Intravenous meropenem has been used effectively in patients with cystic fibrosis and chronic lower respiratory tract infections, either as monotherapy or in combination with other antibacterial agents. Eradication of the organism was not always established. It is also indicated, in children over 3 months of age, for the treatment of the above mentioned infections apart from gynaecological infections, infections of the skin and soft tissues and the non-complicated urinary tract infections. Meropenem (Merozan) has proved efficacious alone or in combination with other antimicrobial agents in the treatment of polymicrobial infections.

Adults: The dosage and duration of therapy shall be established depending on type and severity of infection and the condition of the patient. The recommended daily dosage is as follows: 500 mg IV every 8 hours in the treatment of pneumonia, urinary tract infections, gynaecological infections such as endometritis and pelvic inflammatory disease, skin and skin structure infections.
1 g IV every 8 hours in the treatment of nosocomial pneumonias, peritonitis, presumed infections in neutropenic patients and septicaemia.
In meningitis and in lung infections in patients with cystic fibrosis, doses of 2 g every 8 hours are recommended.
As with other antibiotics, particular caution is recommended in using meropenem as monotherapy in critically ill patients with known or suspected Pseudomonas aeruginosa lower respiratory tract infection.
Regular susceptibility testing is recommended when treating Pseudomonas aeruginosa infection.
Meropenem (Merozan) should be administrated by intravenous bolus injection over approximately 5 minutes or by intravenous infusion over approximately 15-30 minutes (See Caution for Usage and Storage).
Dosage Schedule for Adults with Impaired Renal Function: Dosage should be reduced in patients with creatinine clearance less than 51 ml/min, as scheduled as follows. (See Table 2.)

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Meropenem is cleared by haemodialysis. If continued treatment with Meropenem (Merozan) is necessary, it is recommended that the unit dose (based on the type and severity of infection) is administered at the completion of the haemodialysis procedure to restore therapeutically effective plasma concentrations. There is no experience with the use of meropenem in patients under peritoneal dialysis.
Dosage in Adults with Hepatic Insufficiency: No dosage adjustment is necessary in patients with hepatic insufficiency (See Precautions).
Elderly Patients: No dosage adjustment is required for the elderly with normal renal function or creatinine clearance values above 50 ml/min.
Children: For children over 3 months and up to 12 years of age the recommended dose is 10 to 40 mg/kg every 8 hours depending on type and severity of infection, susceptibility of the pathogen and the condition of the patient. In children over 50 kg weight, adult dosage should be used. In neutropenic patients with fever, the recommended dose is 20 mg/kg every 8 hours. In meningitis and in cystic fibrosis, the recommended dose is 40 mg/kg every 8 hours. Meropenem (Merozan) should be administrated by intravenous bolus injection over approximately 5 minutes or by intravenous infusion over approximately 15-30 minutes. There is no experience in children with renal impairment.
Reconstitution, Compatibility and Stability: Meropenem solutions for bolus intravenous injection should be dissolved in water for injections (5 ml per 250 mg meropenem). This provides an approximate concentration of 50 mg/ml. Solutions are clear, and colourless or pale yellow. Meropenem solutions for intravenous infusion can be prepared with 50 to 200 ml of Sodium chloride 0.9% w/v or any other compatible infusion fluid (See Storage). Freshly prepared solutions are recommended, however solutions of Meropenem (Merozan) can be stored at room temperature (≤25°C) or under refrigeration (at 4°C) (See Storage). Meropenem (Merozan) should not be mixed or added to other medicines. Solutions of Meropenem (Merozan) should not be frozen.

Accidental overdosage could occur during therapy, particularly in patients with renal impairment. Treatment of overdosage should be symptomatic. In normal individuals, rapid renal elimination will occur. In patients with renal impairment, haemodialysis will remove meropenem and its metabolite.

Meropenem (Merozan) is contraindicated in patients who have demonstrated hypersensitivity to meropenem or to carbapenems, penicillins or other beta-lactam antibiotics.

Patients who had experienced hypersensitivity reactions to carbapenems, penicillins or other beta-lactam antibiotics may demonstrate hypersensitivity to meropenem as well. 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, therefore, continuous monitoring of each patient is necessary.
Use in infections caused by methicillin resistant staphylococci is not recommended. Rarely, pseudomembranous colitis has been reported on meropenem as with practically all antibiotics. Therefore, it is important to consider the diagnosis of pseudomembranous colitis in the case of patients who develop diarrhoea in association with the use of Meropenem (Merozan).
The co-administration of Meropenem (Merozan) with potentially nephrotoxic drugs should be considered with caution. For dosage see Dosage & Administration.
Use in Children: Efficacy and tolerability in infants under 3 months old have not been established; therefore, Meropenem (Merozan) is not recommended for use below this age.
Effects on ability to drive and use machines: No data are available, but it is not anticipated that Meropenem (Merozan) will affect the ability to drive and use machines.

Pregnancy: The safety of Meropenem (Merozan) in human pregnancy has not been established. Animal studies have not shown any adverse effect on the developing foetus. Meropenem (Merozan) should not be used in pregnancy unless the potential benefit justifies the potential risk to the foetus. In every case, it should be used under the direct supervision of a physician.
Lactation: Meropenem is detectable at very low concentrations in animal breast milk. Meropenem (Merozan) should not be used in breast-feeding women unless the potential benefit justifies the potential risk to the baby.

Meropenem (Merozan) is generally well tolerated and adverse effects rarely require discontinuation of the treatment.
Serious adverse events are rare. Most of the following adverse events have been reported in less than 1% of the patients: Local intravenous injection site reactions: Inflammation, thrombophlebitis, pain at the site of injection.
Systemic allergic reactions: Rarely, systemic allergic reactions (hypersensitivity) may occur following administration of Meropenem (Merozan). These reactions may include angioedema and manifestations of anaphylaxis.
Skin reactions: Rash, pruritus, urticaria. Rarely, severe skin reactions such as erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis have been observed.
Gastrointestinal tract: Abdominal pain, nausea, vomiting, diarrhoea.
Blood: thrombocythaemia, eosinophilia, thrombocytopenia, leucopenia and neutropenia (including very rare cases of agranulocytosis). A positive direct or indirect Coombs test may develop in some patients. There have been also reports of reduction in partial thromboplastin time.
Liver function: Increase in serum levels of bilirubin, transaminases, alkaline phosphatase and lactic dehydrogenase, alone or in combination, have been reported;
Central nervous system: Headache, paraesthesia. Convulsions have been rarely reported but a causal link with meropenem treatment has not been established;
Other: Oral and vaginal candidiasis.

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 meropenem dosed without probenecid are adequate, the co-administration of probenecid with meropenem is not recommended.
The potential effect of meropenem on the protein binding of other drugs or metabolism has not been studied. The protein binding of meropenem is low and therefore no interactions with other compounds based on displacement from plasma proteins would be expected. Meropenem has been administered concomitantly with other medications without adverse pharmacological interactions. Meropenem may reduce serum valproic acid levels and therefore subtherapeutic levels may be reached in some patients. However, no other specific data regarding potential drug interactions is available apart from probenecid.

Incompatibilities: Meropenem (Merozan) is compatible with the infusion fluids referred in Storage. Meropenem (Merozan) should not be mixed or added to other medicines.
Special precautions for disposal and other handling: See Dosage & Administration.
Standard aseptic technique should be employed during reconstitution. Shake constituted solution before use.
Shelf-life: The expiration date is indicated on the outer carton and on the vial label. Do not use this medicine after the expiration date.
Standard aseptic technique should be employed during reconstitution. Shake constituted solution before use.
All vials are for single use only.

Store at temperatures not exceeding 30°C. Freshly prepared solutions are recommended, however solutions of Meropenem (Merozan) can be stored at room temperature (≤25°C) or under refrigeration (at 4°C). The stability periods of solutions of Meropenem (Merozan) are shown in the following table: (See Table 3.)

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Meropenem (Merozan) solutions should not be frozen.

Other Beta-Lactams

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

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