Meronem^® (Powder) Instructions for Use

Marketing Authorization Holder

Pfizer, Inc. (USA)

Manufactured By

Sumitomo Pharmaceuticals, Co. Ltd. (Japan)

Or

ACS Dobfar, S.p.A. (Italy)

Packaging and Quality Control Release

ZAMBON SWITZERLAND, Ltd. (Switzerland)

ATC Code

J01DH02 (Meropenem)

Active Substance

Meropenem (Rec.INN registered by WHO)

Dosage Forms

	Meronem®	Powder for solution for intravenous administration 0.5 g: vial 10 pcs.
		Powder for solution for intravenous administration 1 g: vial 10 pcs.

Dosage Form, Packaging, and Composition

Powder for solution for intravenous administration from white to light yellow.

Excipients : anhydrous sodium carbonate – 104 mg.

Vials with a capacity of 20 ml (10) – cardboard packs with first opening control.

Powder for solution for intravenous administration from white to light yellow.

Excipients : anhydrous sodium carbonate – 208 mg.

Vials with a capacity of 30 ml (10) – cardboard packs with first opening control.

Clinical-Pharmacological Group

Antibiotic of the carbapenem group

Pharmacotherapeutic Group

Antibiotic-carbapenem

Pharmacological Action

An antibiotic from the carbapenem group for parenteral use, resistant to human dehydropeptidase-1 (DHP-1), does not require additional administration of a DHP-1 inhibitor.

Meropenem exerts a bactericidal effect by affecting the synthesis of the bacterial cell wall. The powerful bactericidal action of meropenem against a wide range of aerobic and anaerobic bacteria is explained by its high ability to penetrate the bacterial cell wall, high level of stability to most β-lactamases, and significant affinity for penicillin-binding proteins (PBPs). Minimum bactericidal concentrations (MBC) are usually the same as minimum inhibitory concentrations (MIC). For 76% of the tested bacterial species, the MBC/MIC ratio was 2 or less.

Meropenem is stable in pathogen susceptibility tests. In vitro tests show that Meropenem acts synergistically with various antibiotics. It has been shown in vitro and in vivo that Meropenem has a post-antibiotic effect.

The only recommended criteria for susceptibility to meropenem are based on the pharmacokinetics of the drug and on the correlation of clinical and microbiological data – zone diameter and MIC, determined for the relevant pathogens.

The spectrum of antibacterial activity of meropenem, determined in vitro, includes almost all clinically significant gram-positive and gram-negative aerobic and anaerobic microorganisms.

The drug is active against aerobic gram-positive bacteria Bacillus spp., Corynebacterium diphtheriae, Enterococcus liquefaciens, Enterococcus avium, Listeria monocytogenes, Lactobacillus spp., Nocardia asteroides, Staphylococcus aureus (penicillinase-producing and non-producing strains), coagulase-negative staphylococci, incl. Staphylococcus saprophyticus, Staphylococcus capitis, Staphylococcus cohnii, Staphylococcus xylosus, Staphylococcus warneri, Staphylococcus hominis, Staphylococcus simulans, Staphylococcus intermedius, Staphylococcus sciuri, Staphylococcus lugdunensis, Streptococcus pneumoniae (penicillin-sensitive and resistant), Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus equi, Streptococcus bovis, Streptococcus mitis, Streptococcus mitior, Streptococcus milleri, Streptococcus sanguis, Streptococcus viridans, Streptococcus salivarius, Streptococcus morbillorum, group G streptococci, group F streptococci, Rhodococcus equi; aerobic gram-negative bacteria Achromobacter xylosoxidans, Acinetobacter anitratus, Acinetobacter lwoffii, Acinetobacter baumannii, Aeromonas hydrophila, Aeromonas sorbria, Aeromonas caviae, Alcaligenes faecalis, Bordetella 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 β-lactamase-producing strains and ampicillin-resistant strains), Haemophilus parainfluenzae, Haemophilus ducreyi, Helicobacter pylori, Neisseria meningitidis, Neisseria gonorrhoeae (including β-lactamase-producing strains and strains resistant to penicillin and spectinomycin), Hafnia alvei, Klebsiella pneumoniae, Klebsiella aerogenes, Klebsiella ozaenae, Klebsiella oxytoca, Moraxella 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 pseudomallei, Pseudomonas acidovorans, Salmonella spp., including Salmonella enteritidis, Salmonella 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 spp., Bacteroides fragilis, Bacteroides vulgatus, 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 urealyticus, Prevotella oris, Prevotella buccae, Prevotella denticola, Prevotella levii, Porphyromonas asaccharolyticus, Bifidobacterium spp., Bilophila wadsworthia, Clostridium perfringens, Clostridium bifermentans, Clostridium ramosum, Clostridium sporogenes, Clostridium cadaveris, 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 anaerobius, Peptostreptococcus micros, Peptostreptococcus saccharolyticus, Peptococcus saccharolyticus, Peptococcus asaccharolyticus, Peptostreptococcus magnus, Peptostreptococcus prevotii, Propionibacterium acnes, Propionibacterium avidium, Propionibacterium granulosum.

The following are resistant to the drug: Stenotrophomonas maltophilia, Enterococcus faecium and methicillin-resistant staphylococci.

Meronem^® has shown efficacy as monotherapy or in combination with other antimicrobial agents in the treatment of polymicrobial infections.

Pharmacokinetics

Distribution

IV administration over 30 minutes of a single dose of the drug to healthy volunteers results in a C_max of approximately 11 µg/ml for a 250 mg dose, 23 µg/ml for a 500 mg dose, and 49 µg/ml for a 1 g dose. However, there is no absolute pharmacokinetic proportional dependence on the administered dose for either C_max or AUC. Moreover, a decrease in plasma clearance from 287 to 205 ml/min was observed for doses from 250 mg to 2 g.

IV bolus injection over 5 minutes of a single dose of Meronem^® to healthy volunteers results in a C_max of approximately 52 µg/ml for a 500 mg dose and 112 µg/ml for a 1 g dose.

C_max in plasma upon IV administration of 1 g of the drug over 2 minutes, 3 minutes, and 5 minutes was 110, 91, and 94 µg/ml, respectively.

Binding to plasma proteins is approximately 2%. Meropenem penetrates well into most body tissues and fluids, including the cerebrospinal fluid of patients with bacterial meningitis, reaching concentrations exceeding those required to suppress most bacteria.

Six hours after IV administration of 500 mg, the plasma level of meropenem decreases to values of 1 µg/ml or less. With repeated administration of doses at 8-hour intervals in patients with normal renal function, no accumulation of meropenem occurs.

Metabolism and Excretion

The only metabolite of meropenem is microbiologically inactive.

Approximately 70% of the administered dose is excreted unchanged in the urine within 12 hours, after which further urinary excretion is insignificant. A meropenem concentration in urine exceeding 10 µg/ml is maintained for 5 hours after administration of a 500 mg dose. With regimens of 500 mg every 8 hours or 1 g every 6 hours, no accumulation of meropenem in plasma and urine was observed in volunteers with normal liver function. In patients with normal renal function, T_1/2 is approximately 1 hour.

Pharmacokinetics in Special Clinical Cases

The pharmacokinetic parameters of Meronem^® in children are the same as in adults. T_1/2 of meropenem in children under 2 years of age is approximately 1.5-2.3 hours, and linear pharmacokinetics is observed in the dose range of 10-40 mg/kg.

Pharmacokinetic studies of the drug in patients with renal failure showed that the clearance of meropenem correlates with creatinine clearance. In such patients, dose adjustment is necessary.

Pharmacokinetic studies of the drug in elderly patients showed a decrease in meropenem clearance, which correlated with the decrease in creatinine clearance associated with age.

Pharmacokinetic studies of the drug in patients with liver diseases showed that liver diseases do not affect the pharmacokinetics of meropenem.

Indications

Treatment of the following infections in children and adults caused by one or more pathogens sensitive to the drug

• Pneumonia (including hospital-acquired);
• Urinary tract infections;
• Abdominal infections;
• Gynecological infections (such as endometritis and inflammatory pelvic diseases);
• Skin and soft tissue infections;
• Meningitis;
• Septicemia;
• Empirical therapy for suspected bacterial infection in adult patients with febrile episodes against the background of neutropenia, as monotherapy or in combination with antiviral or antifungal drugs.

ICD codes

Dosage Regimen

For adults, the dosing regimen and duration of therapy are established depending on the type and severity of the infection and the patient’s condition. The following daily doses are recommended.

For treatment of pneumonia, urinary tract infections, gynecological infections (endometritis and inflammatory pelvic diseases), skin and soft tissue infections – 500 mg IV every 8 hours.

For treatment of hospital-acquired pneumonia, peritonitis, suspected bacterial infection in patients with neutropenia, as well as septicemia – 1 g IV every 8 hours.

For treatment of meningitis – 2 g IV every 8 hours.

In patients with impaired renal function with a CC of 50 ml/min or less, doses should be reduced as follows.

Meropenem is removed by hemodialysis, therefore, if continuation of treatment is required, it is recommended that a unit dose (determined depending on the type and severity of the infection) be administered upon completion of the hemodialysis procedure to restore effective plasma concentration.

There is no experience with the use of Meronem^® in patients undergoing peritoneal dialysis.

In patients with hepatic insufficiency, no dose adjustment is necessary.

In elderly patients with normal renal function or CC greater than 50 ml/min, no dose adjustment is required.

For children aged 3 months to 12 years, the recommended dose for IV administration is 10-20 mg/kg every 8 hours depending on the type and severity of the infection, the sensitivity of the pathogenic microorganism, and the patient’s condition. In children weighing more than 50 kg, the same doses as for adults should be used.

For meningitis, the recommended dose is 40 mg/kg every 8 hours.

Rules for preparation and administration of the solution

Meronem^® should be administered as an IV bolus injection over at least 5 minutes or as an IV infusion over 15-30 minutes.

For IV bolus injections, Meronem^® should be diluted with sterile water for injections (5 ml per 250 mg of meropenem), which provides a solution concentration of 50 mg/ml.

For IV infusions, Meronem^® should be diluted with sterile water for injections or a compatible infusion fluid and then further diluted (to 50-200 ml) with a compatible infusion fluid.

Meronem^® is compatible with the following infusion fluids: 0.9% sodium chloride solution for IV infusion; 5% or 10% glucose solution for IV infusion; 5% glucose solution for IV infusion with 0.02% sodium bicarbonate solution; 0.9% sodium chloride solution with 5% glucose solution for IV infusion; 5% glucose solution with 0.225% sodium chloride solution for IV infusion; 5% glucose solution with 0.15% potassium chloride solution for IV infusion; with 2.5% or 10% mannitol solution for IV infusion.

Meronem^® should not be mixed with solutions containing other drugs.

Before use, the diluted solution should be shaken. All vials are for single use only. Standard aseptic rules must be applied when diluting Meronem^®.

Adverse Reactions

Severe adverse effects are rarely observed. The following adverse effects have been reported.

Allergic reactions rarely – angioedema, anaphylactic reactions.

Dermatological reactions itching, rash, urticaria; rarely – multiforme (exudative) erythema, Stevens-Johnson syndrome and toxic epidermal necrolysis.

From the digestive system abdominal pain, nausea, vomiting, diarrhea; in some cases – reversible increase in blood levels of bilirubin, transaminases, alkaline phosphatase and LDH individually or in combination; in some cases – pseudomembranous colitis.

From the hematopoietic system reversible thrombocytosis, eosinophilia, thrombocytopenia, leukopenia and neutropenia (including very rare cases of agranulocytosis). Some patients may have a positive direct or indirect Coombs test; there are also reports of cases of decreased partial thromboplastin time.

From the CNS and peripheral nervous system headache, paresthesia; there are reports of seizures, however, a causal relationship with the intake of Meronem^® has not been established.

Local reactions inflammation, thrombophlebitis, pain at the injection site.

Effects due to biological action oral candidiasis, vaginal candidiasis.

Contraindications

• Hypersensitivity to the drug.

With caution the drug should be prescribed simultaneously with potentially nephrotoxic drugs, as well as to patients with symptoms of dyspepsia, especially associated with colitis.

Use in Pregnancy and Lactation

The safety of Meronem^® use during pregnancy has not been studied.

Experimental studies in animals have not shown any adverse effects on the developing fetus. The only adverse event identified in animal studies on the effect of the drug on the reproductive system was an increased frequency of abortions in monkeys when administered a dose 13 times higher than the recommended human dose.

Meronem^® should not be used during pregnancy unless the potential benefit from its use justifies the possible risk to the fetus. In each case, the drug should be used under the direct supervision of a physician.

Meropenem is determined in animal breast milk in very low concentrations. Meronem^® should not be used during lactation (breastfeeding) unless the potential benefit from its use justifies the possible risk to the child. If it is necessary to use the drug during lactation, the issue of stopping breastfeeding should be considered.

Use in Hepatic Impairment

In patients with hepatic insufficiency, no dose adjustment is necessary. The use of Meronem^® in patients with liver disease should be carried out under careful monitoring of transaminase and bilirubin levels.

Use in Renal Impairment

In patients with impaired renal function with a creatinine clearance of 51 ml/min and less, doses should be reduced as follows.

Pediatric Use

For children aged 3 months to 12 years, the recommended dose for intravenous administration is 10-20 mg/kg every 8 h depending on the type and severity of the infection, the sensitivity of the pathogen and the patient’s condition. In children weighing more than 50 kg, the same doses as for adults should be used.

For meningitis, the recommended dose is 40 mg/kg every 8 h.

The efficacy and tolerability of Meronem^® in children under 3 months of age have not been established, therefore the drug is not recommended for use in children under 3 months.

Geriatric Use

In elderly patients with normal renal function or CC greater than 50 ml/min, no dose adjustment is required.

Special Precautions

As with other antibiotics, when using meropenem as monotherapy in critically ill patients with known or suspected lower respiratory tract infection caused by Pseudomonas aeruginosa, regular determination of pathogen sensitivity is recommended.

Pseudomembranous colitis is observed with the use of almost all antibiotics and can vary in intensity from mild to life-threatening forms. Therefore, antibiotics should be prescribed with caution to persons with gastrointestinal complaints, especially patients with colitis. It is important to keep in mind the diagnosis of “pseudomembranous colitis” in case of diarrhea during antibiotic administration. Although studies have shown that the toxin produced by Clostridium difficile is one of the main causes of antibiotic-associated colitis, other causes should also be kept in mind.

There are clinical and laboratory signs of partial cross-hypersensitivity between other carbapenems and beta-lactam antibiotics, penicillins and cephalosporins. Although allergic reactions with the use of beta-lactam antibiotics were quite common, hypersensitivity reactions during the administration of Meronem^® have been rarely reported. Before starting therapy with meropenem, it is necessary to carefully interview the patient, paying special attention to a history of hypersensitivity reactions to beta-lactam antibiotics. Meronem^® should be used with caution in patients with a history of such events. If an allergic reaction to Meropenem occurs, the drug should be discontinued and appropriate measures taken.

The use of Meronem^® in patients with liver disease should be carried out under careful monitoring of transaminase and bilirubin levels.

As with other antibiotics, predominant growth of non-susceptible microorganisms is possible, and therefore constant monitoring of each patient is necessary.

Use for infections caused by methicillin-resistant staphylococcus is not recommended.

Use in pediatrics

The efficacy and tolerability of Meronem^® in children under 3 months of age have not been established, therefore the drug is not recommended for use in children under 3 months.

There is no experience with the use of the drug in pediatric practice in patients with neutropenia or with primary or secondary immunodeficiency.

There is no experience with the use of Meronem^® in children with impaired liver and kidney function.

The efficacy and tolerability of Meronem^® in children under 3 months of age have not been established, therefore the drug is not recommended for use in children under 3 months.

Effect on ability to drive vehicles and mechanisms

Meronem^® does not affect the ability to drive a car and other machinery.

Overdose

Accidental overdose is possible during treatment, especially in patients with impaired renal function.

Treatment symptomatic therapy is performed. Normally, the drug is rapidly eliminated by the kidneys. In patients with renal impairment, hemodialysis effectively removes Meropenem and its metabolites.

Drug Interactions

Probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion of meropenem, causing an increase in its half-life and plasma concentration. Because the efficacy and duration of action of Meronem^® without probenecid are adequate, co-administration of probenecid with Meronem^® is not recommended.

The possible effect of Meronem^® on the metabolism and protein binding of other drugs has not been studied. However, given the low binding of meropenem to plasma proteins (about 2%), it can be assumed that there should be no interaction with other drugs.

Meronem^® was administered during the intake of other drugs, and no adverse pharmacological interactions were noted.

Meronem^® may decrease the serum level of valproic acid. In some patients, a level below the therapeutic level may be achieved.

However, there are no specific data on possible drug interactions.

Storage Conditions

List B. The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 4 years.

It is recommended to use a freshly prepared solution of Meronem^® for intravenous injections and infusions, however, diluted Meronem^® retains satisfactory efficacy when stored at room temperature (not higher than 25°C (77°F)) or in a refrigerator (at 4°C (39.2°F)) within the time limits indicated in the table.

The solution of Meronem^® should not be frozen.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.