Meromax

Meromax

meropenem

Manufacturer:

Mepro Pharma

Distributor:

Royal Distribution

Marketer:

ESTI Pharma
Full Prescribing Info
Contents
Meropenem.
Description
Each vial contains: Meropenem USP equivalent to Meropenem (anhydrous) 500 mg or 1 g, sodium (as sodium carbonate) 45.1 or 90.2 mg.
Action
Pharmacology: Pharmacodynamics: Mechanism of action: Meropenem is a carbapenem antibiotic for parenteral use, that is relatively stable to human dehydropeptidase-1 (DPH-1) and therefore does not require the addition of an inhibitor of DPH-1.
Pharmacokinetics: A 30-min IV infusion of a single dose of Meromax in healthy volunteers in peak plasma levels of approximately 11 mcg/mL for the 250-mg dose. 23 mcg/mL for the 500-mg dose and 49 mcg/mL for the 1-g 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-min IV bolus injection of Meromax in healthy volunteers results in peak plasma levels of approximately 52 mcg/mL for the 500 mg dose and 112 mcg/mL for the 1-g dose. IV infusions of 1 g over 2, 3 and 5 min were compared in a 3-way crossover trial. These duration of infusion resulted in peak plasma levels of 110, 91 and 94 mcg/mL, respectively. After an IV dose of 500 mg, plasma levels of Meropenem decline to values of ≤1 mcg/mL, 6 hours after administration. When multiple doses are administered at 8-hrly intervals to subjects with normal renal function accumulation of Meropenem does not occur.
In subjects with normal renal function, Meropenem elimination half-life is approximately 1 hr plasma protein-binding is approximately 2%. Approximately 70% of the administered dose is recovered as unchanged Meropenem in the urine over 12 hrs, after which little further urinary excretion is detectable. Urinary concentrations of Meropenem in excess of 10 mcg/mL are maintained for up to 5 hrs after administration of a 500-mg dose. No accumulation of Meropenem in plasma or urine was observed with regimens using 500 mg administered every 8 hrs or 1 g administered every 6 hrs 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 Meromax in children are similar to those in adults. The elimination half-life for Meropenem was approximately 1.5-2.3 hrs in children <2 years and the pharmacokinetics are linear over the dose range of 10-40 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 subjects 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, Meromax has shown nephrotoxic effects, only at high dose levels (500 mg/kg).
Effects on the central nervous system: 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 >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 dose 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 Meromax in juveniles compared to all adult animals. The IV formulation was well tolerated in animal studies.
The sole metabolite of Meromax had similar profile toxicity in animal studies.
Microbiology: Meropenem exerts its bactericidal action by interfering with vital bacterial cell wall synthesis. The ease with which it penetrates bacterial cell walls, its higher level of stability to all serine β-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. Minimum bactericidal concentrations (MBC) are commonly the same as the minimum inhibitory concentrations (MICs). For 76% of the bacteria tested, the MBC, MIC ratios were ≤2.
Meropenem is stable in susceptibility tests and these tests can be performed using the normal routine methods, In vitro tests show that Meropenem acts synergistically with various antibiotics. It has been demonstrated both in vitro that Meropenem has a post-antibiotic effect.
A single set of Meropenem susceptibility criteria are recommended based on pharmacokinetics and correlation of clinical and microbiological outcomes with zone diameter and MIC of the infecting organisms. (See Table 1.)

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The in vitro antibacterial spectrum of Meropenem includes the majority of clinically gram positive and negative aerobic and anaerobic strains of bacteria as follows: Gram-Positive Aerobes: Bacillus sp, Corynebacterium diphtheriae, Enterococcus faecalis, Enterococcus liquifaciens, Enterococcus avium, Listeria monocytogenes, Lactobacillus sp, 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 morbillorium, Streptococcus group G, Streptococcus group F, Rhodococcus equi.
Gram-Negative Aerobes: Achromobacter xylosoxidans, Acinetobacter anitratus, Acinobacter lwoffi, Acinobacter baumannii, Aeromonas hydrophila, Aeromonas sobria, Aeromonas caviae, Alcaligenes faecalis, Bordetella bronchiseptica, Brucella melitensis, Campylobacter coli, Campylobacter jejuni, Citrobacter freundii, Citrobacter diversus, Citrobacter koseri, Citrobacter amalonaticus, Enterobacter aerogenes, Enterobacter (Pantoea) agglomerans, Enterobacter cloacae, Enterobacter sakazakii, Escherichia coli, Escherichia hermannii, Gardnerella vaginalis, Haemophilus influenzae (including β-lactamase positive and ampicillin-resistant strains), Haemophilis parainfluenzae, Haemophilus ducreyi, Helicobacter pylori, Neisseria meningitidis, Neisseria gonorrhoeae (including β-lactamase positive, penicillin-resistant and spectinomycin-resistant strains), Hafnia alvei, Klebsiella pneumoniae, Klebsiella aerogenes, Klebsiella ozaenae, Klebsiella oxytoca, Moraxella (Branhemella) catarrhalis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Proteus penneri, Providencia rettgeri, Providencia stuartii, Providencia alcalifaciens, Pasteurella multicoda, Plesiomonas shigelloides, Pseudomonas aeruginosa, Pseudomonas putida, Pseudomonas alcaligenes, Burkholderia (Pseudomonas) cepacia, Pseudomonas flourescens, Pseudomonas stutzeri, Pseudomonas pseudomallei, Pseudomonas acidovorans, Salmonella sp (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, Bacteroides-Prevotella-Porphyromonas sp, Bacteroides fragilis, Bacteroides vulgaris, Bacteroides variabilis, Bacteroides pneumosintes, Bacteroides coagulans, Bacteroides uniformis, Bacteroides distasonis, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides eggerthii, Bacteroides capsillosis, Prevotella buccalis, Prevotella corporis, Bacteroides gracilis, Prevotella melaninogenica, Prevotella intermedia, Prevotella bivia, Prevotella splanchnicus, Prevotella oralis, Prevotella disiens, Prevotella rumenicola, Prevotella ureolyticus, Prevotella buccae, Prevotella denticola, Bacteroides levii, Porphyromonas asaccharolytica, Bifidobacterium sp, Bilophila wadsworthia, Clostridium perfringens, Clostridium bifermentans, Clostridium ramosum, Clostridium sporogenes, Clostridium cadaveris, Clostridium sordellii, Clostridium butyricum, Clostridium clostridiformis, Clostridium innocuum, Clostridium subteminale, Clostridium tertium, Eubacterium lentum, Eubacterium aerofaciens, Fusobacterium mortiferum, Fusobacterium necrophorum, Fusobacterium nucleatum, Fusobacterium varium, Mobilincus curtisii, Mobiluncus mulieris, Peptostreptococcus anaerobius, Peptostreptococcus micros, Peptostreptococcus saccharolyticus, Peptococcus saccharolyticus, Peptostreptococcus asaccharolyticus, Peptostreptococcus magnus, Peptostreptococcus prevotii, Propionibacterium acnes, Propionibacterium avidium, Propionibacterium granulosum.
Stenotrophomonas maltophilia, Enterococcus faecium and methicillin-resistant staphylococci have been found to be resistant to Meropenem.
Indications/Uses
For treatment in adults and children of the following infections caused by single or multiple bacteria to meropenem: Pneumonias and nosocomial pneumonias; urinary tract and intra-abdominal infections; gynaecological infections e.g. endometritis and pelvic inflammatory disease, bacterial meningitis; septicaemia. Empiric treatment for presumed infections in patients with febrile neutropenia used as monotherapy or in combination with antiviral or antifungal agents.
Meromax has proved efficacious alone or in combination with other antimicrobial agents in the treatment of polymicrobial infections.
Dosage/Direction for Use
Adults: The dosage and duration of therapy shall be established depending on type and severity of infection and the condition of the patient.
Pneumonia, UTI, Gynaecological infections e.g. Endometritis: Recommended Daily Dose: 500 mg IV every 8 hrs.
Hospital-Acquired Pneumonia, Peritonitis, Presumed Infections in Febrile Neutropenic Patients, Septicaemia: 1 g IV every 8 hrs.
Meningitis: Recommended Dose: 2 g every 8 hrs.
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 infection.
Regular sensitivity testing is recommended when treating Pseudomonas aeruginosa infection.
Renal Impairment: Dosage should be reduced in patients with creatinine clearance <51 mL/min, scheduled as follows. (See Table 2.)

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Meropenem is cleared by haemodialysis. If continued treatment with Meromax 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 in the use of Meromax in patients undergoing peritoneal dialysis.
Hepatic insufficiency: No dosage adjustment is necessary in patients with hepatic insufficiency (see Precautions).
Children >3 months and up to 12 years: Recommended Dose: 10-20 mg/kg every 8 hrs depending on type and severity of infection, susceptibility of the pathogens and the condition of the patient. Children >50 kg weight: Adult dosage should be used.
Meningitis: recommended dose: 40 mg/kg/every 8 hrs.
Febrile Episodes in Neutropenic Patients: 20 mg/kg every 8 hrs.
There is no experience in children with renal impairment.
Elderly: No dosage adjustment is required for the elderly with normal renal function or creatinine clearance values >50 mL/min.
Administration: Meromax can be given as a bolus IV injection over approximately 5 min or by IV infusion over approximately 15-30 min.
Meromax to be used for bolus IV injection should be constituted with sterile water for injections (5 mL per Meropenem 250 mg). This provides an approximate concentration of 50 mg/mL. Constituted solutions are clear and colourless or pale yellow.
Compatibilities: Meromax for IV infusion may be constituted with compatible infusion fluids (50-200 mL).
Meromax is compatible with the following infusion fluids: 0.9% sodium chloride solution; 5% or 10% glucose solution; 5% glucose solution with 0.02% sodium bicarbonate; 0.9% sodium chloride and 5% glucose solution; 5% glucose with 0.225% sodium chloride solution; 5% glucose with 0.15% potassium chloride solution; 2.5% or 10% Mannitol solutions. Meromax should not be mixed with or added to other drugs.
Administer by IV injection or infusion: IV Injection: Reconstitution and Dilution: Reconstitute single-use vials containing 1 g with 10 or 20 mL, respectively, of sterile water for injection to provide a solution containing approximately 50 mg/mL. The vial should be shaken until dissolution occurs and then allowed to stand until the solution is clear.
Rate of Administration: The appropriate dose of reconstituted solution should be injected over a period of 3-5 minutes.
IV Infusion: Reconstitution and Dilution: Reconstitute infusion vials containing 1 g with a compatible IV solution (e.g., 0.9% sodium chloride, 5% dextrose) to provide solutions containing approximately 50 mg/mL. Alternatively, reconstitute vials containing 1 g with 10 or 20 mL, respectively, of sterile water for injection and then compatible IV.
Rate of Administration: Infuse IV over 15-30 minutes.
Shake constituted solution before use.
Overdosage
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 subjects with renal impairment, haemodialysis will remove Meropenem and its metabolite.
Contraindications
Hypersensitivity to Meropenem.
Special Precautions
There is some clinical and laboratory evidence of partial cross-allergenicity between other carbapenems and β-lactam antibiotics penicillins and cephalosporins. As with all β-lactam antibiotics, rare hypersensitivity reactions have been reported (see Adverse Reactions). Before initiating therapy with Meropenem, careful inquiry should be made concerning previous hypersensitivity reactions to β-lactam antibiotics. Meromax should be used with caution in patients with such a history. If an allergic reaction to Meropenem occurs, the drug should be discontinued and appropriate measures taken.
Use of Meropenem in patients with hepatic disease should be made with careful monitoring of transaminase and bilirubin levels.
As with other antibiotics, overgrowth of non susceptible organisms may occur and therefore, continuous monitoring of each patients 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 and may vary in severity from slight to life threatening. Therefore, antibiotics should be prescribed with care for individuals with a history of gastrointestinal complaints, particularly colitis. It is important to consider the diagnosis of pseudomembranous colitis in patients who develop diarrhea in association with the use of Meropenem. Although studies indicate that a toxin produced by Clostridium difficile is one of the main causes of antibiotic associated colitis, other causes should be considered.
The co-administration of Meromax with potentially nephrotoxic drugs should be considered with caution (see Dosage & Administration).
Effects on the ability to drive or operate machinery: No data is available but it is not anticipated that Meromax will affect the ability to drive or operate machinery.
Use in children: Efficacy and tolerability in infants <3 months have not been established. Therefore, Meromax is not recommended for use below this age.
There is no experience in children with altered hepatic renal function.
Use In Pregnancy & Lactation
Use in pregnancy: Pregnancy Category (US FDA): Category B: Either animal-reproduction studies have not demonstrated a foetal risk but there are no controlled studies in pregnant women or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women the first trimester (and there is no evidence of a risk in later trimesters).
The safety of Meromax in human pregnancy has not been evaluated. Animal studies have not shown any adverse effect on the developing foetus. The only adverse effect observed in animal reproductive studies was an increased incidence of abortions in monkeys at 13 times the expected exposure in man.
Meromax 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 the physician.
Use in lactation: Meropenem is detectable at very low concentrations in animal breast milk. Meromax should not be used in breastfeeding women unless the potential benefit justifies the potential risk to the baby.
Adverse Reactions
Serious adverse events are rare. During clinical trials, the following adverse events were reported.
Local IV 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. These reactions may include angioedema and manifestations of anaphylaxis.
Skin Reactions: Rash, pruritus, urticaria. Rarely, severe skin reactions eg, erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis have been observed.
Gastrointestinal: Abdominal pain, nausea, vomiting, diarrhoea. Pseudomembranous colitis has been reported.
Blood: Reversible thrombocythaemia, eosinophilia, thrombocytopenia, leucopenia and neutropenia (including very rare cases of agranulocytosis), haemolytic anaemia. A positive direct or indirect Coomb's test may develop in some subjects. There have been reports of reduction in partial thromboplastin time.
Liver Function: Increases in serum concentrations of bilirubin, transaminases, alkaline phosphatase and lactic dehydrogenase alone or in combination have been reported.
Central Nervous System: Headache, paraesthesia. Convulsions have been reported although a causal relationship with meropenem has not been established.
Others: Oral and vaginal candidosis.
Drug Interactions
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, 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 (approximately 2%) and therefore, no interaction with other compounds based on displacement from plasma proteins would be expected. Meropenem may reduce serum Valproic Acid levels. Subtherapeutic levels may be reached in some patients.
Meropenem has been administered concomitantly with other medications without adverse pharmacological interactions. However, no specific data regarding potential drug interactions is available (apart from probenecid as mentioned previously).
Caution For Usage
It is recommended to use freshly prepared solutions of Meromax injection and infusion. Reconstituted solutions of Meromax maintain satisfactory potency at room temperature (up to 15 to 25°C) or in a refrigerator (2 to 8°C) as shown in Table 3.

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MIMS Class
ATC Classification
J01DH02 - meropenem ; Belongs to the class of carbapenems. Used in the systemic treatment of infections.
Presentation/Packing
Inj (vial) 500 mg (+ water for inj) x 20 mL x 1's. 1 g (+ water for inj) x 30 mL x 1's.
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