INSTRUCTION

for medical use of the preparation

IFEЕM

 

Composition:

Active substance: 1 vial contains meropenem trihydrate equivalent to meropenemanhydrous 1 g;

Additive substances: sodium carbonate anhydrous.

Medicinal form. Powder for preparation of the solution for injections.

Pharmacotherapeutical group. Antimicrobial agents for systemic use.

Beta-lactamic antibiotics. Carbapenemes. АТС code J01D H02.

Clinical characteristics.

Indications.

Infections, caused by susceptible to meropenem microorganisms:

- pneumonias, including hospital-acquired ones;

- infections of urinary tracts;

- intra-abdominal infections;

- gynecological infections, including endometritis;

- infections of skin and soft tissues;

- meningitis;

- septicemia;

- empirical therapy when bacterial infection is suspected in adult patients with febrile neutropenia, as monotherapy or in combination with antiviral or antifungal preparations.

Established efficiency of Ifeem both at single use, and in combination with other antimicrobial agents for treatment of polymicrobial infections.

Intravenous administration of meropenem is effective in patients with cystic fibrosis and chronic infections of lower respiratory tracts as monotherapy or in combination with other antimicrobial agents.

Contraindications.

Hypersensitivity to any component of the preparation. Children under 3 months. Children with liver and kidney dysfunction.

Way of introduction and doses.

Adults

Doses and duration of therapy are determined due to the type and severity of infections, as well as patient’s state.

The recommended daily dose is:

For treatment of pneumonia, infections of urinary tracts, gynecological infections, such as endometritis, infections of skin and soft tissues: 500 mg of Ifeem every 8 hours.

For treatment of hospital-acquired pneumonias, peritonitis, suspected infections in patients with neurtopenia, septicemia: 1 g of Ifeem every 8 hours.

In case of cystic fibrosis the recommended dose is 2 g every 8 hours.

In case of meningitis the recommended dose is 2 g every 8 hours.

Similar to cases with other antibiotics it is necessary to be especially careful when using meropenem as monotherapy in seriously ill patients with known or suspectedPseudomonas aeruginosa infection of low respiratory tracts.

For treatment of Pseudomonas aeruginosa infections it is necessary to conduct sensitivity test regularly.

Dosing scheme for adult patients with insufficient renal function.

In patients with creatinine clearance below 51 ml/min, the dose should be reduced according to the following scheme:

Creatinine clearance (ml/min)	Dose (on the basis of dose units of 500 mg, 1 g, and 2 g)	Frequency
26 - 50	One dose unit	every 12 hours
10 - 25	One half of dose unit	every 12 hours
< 10	One half of dose unit	every 24 hours

 

Meropenem is administrated with the help of haemodialysis; if long-term treatment with the preparation is required, it is recommended to introduce a dose unit (due to the type and severity of infections) at the end of haemodialysis procedure in order to restore therapeutically effective plasma concentrations.

There is no experience of Ifeem administration in patients on peritoneal dialysis.

Dosing in patients with hepatic failure

Patients with hepatic failure require no dose correction.

Elderly patients

For elderly patients with normal renal function or creatinine clearance values over 50 ml/min no dose adjustment is necessary.

Children

For children aged between 3 months and 12 years, the recommended dose is 10 - 20 mg/kg every 8 hours depending on the type and severity of infections, sensitivity of the pathogen and patient’s state. In children wit bodyweight over 50 kg, adult dose should be used.

For children aged between 4 and 18 years with cystic fibrosis, as well as for treatment of acute condition of chronic infections of lower respiratory tracts, doses in the range of 25 - 40 mg/kg every 8 hours are used.

In case of meningitis the recommended dose is 40 mg/kg every 8 hours.

Way of administration

Shake the reconstituted solution before administration.

Ifeem may be introduced as an intravenous bolus for approximately 5 min or as an intravenous infusion for approximately 15 - 30 min.

Ifeem for introduction as an intravenous bolus should be dissolved in sterile water for injections (5 ml per 250 mf of meropenem), which results in concentration of 50 mg/ml. The reconstituted solution is transparent and colorless or yellowish color.

Ifeem for introduction as an intravenous infusion may be prepared with the help of compatible liquids for infusion (50 - 200 ml).

Ifeem is compatible with the following liquids for infusion:

0.9 % solution of sodium chloride;

5 % or 10 % glucose solution;

5 % glucose solution with 0.02 % sodium bicarbonate;

5 % glucose solution with 0.9 % sodium chloride;

5 % glucose solution with 0.225 % solution of sodium chloride;

5 % glucose solution with 0.15 % solution of potassium chloride;

2.5 % or 10 % methanol solution.

Side effects.

Ifeem as a rule is well tolerated. Side effects seldom require discontinuation of the therapy. There have been very seldom reports about serious side effects. In order to estimate the frequency of side effect development, the following criteria are used: common (³ 1 %, < 10 %), seldom (³ 0.1 %, < 1 %), and very seldom ( ³ 0.01 %,  0.1 %).

Frequency of development	System organ class	Side effects
Common (³ 1 %, < 10 %)	From the side of blood-vascular system and lymphatic system	Thrombocytopenia
	From the side of nervous system	Headache
	From the side of gastrointestinal tract	Nausea, vomiting, diarrhea, abdominal pain
	From the side of liver and biliary tracts	Increased level of transaminases, alkaline phosphatase, lactate dehydrogenase in serum
	From the side of skin and its derivatives	Skin rash, itching
	General disorders and state of administration site	Inflammation, pain
Seldom (³ 0.1 %, < 1 %)	From the side of blood-vascular system and lymphatic system	Eosinophilia, thrombocytopenia
	From the side of liver and biliary tracts	Increased concentration of bilirubin
Very seldom (³ 0.01 %, < 0.1 %)	From the side of nervous system	Crumps
Frequency is not established	From the side of blood-vascular system and lymphatic system	Leukopenia, neurtopenia, agranulocytosis, hemolytic anemia
	From the side of immune system	Angioneurotic edema, anafilaxia manifestations
	From the side of nervous system	Paresthesia
	From the side of gastrointestinal tract	Pseudomembranous colitis
	From the side of skin and its derivatives	Urticaria, Stevens-Johnson syndrome, erythema multiforme,toxic epidermal necrolysis
	General disorders and state of administration site	Trombophlebitis, oral and vaginal candidiasis

Overdose.

Overdose may develop during treatment, especially in patients with renal disorders. Symptoms of overdose may include increased side effects that are described in Section “Side effects”. Overdose treatment is symptomatic. In patients with no disturbance of renal function, the preparation is excreted quickly with urine. In patients with disturbed of renal function meropenem and its degradation products may be excreted via haemodialysis.

Use in pregnancy and lactation.

Ifeem should not be used during pregnancy and lactation, unless potential benefit for the mother prevails over potential risk for the fetus or the baby.

In each case the preparation should be used under close medical supervision.

Meropenem is found in animal breast milk in very low concentrations.

Children.

The preparation is not used in children aged under 3 months and in those with disturbed hepatic and renal function.

There is no experience of use in children with neutropenia, primary or secondary immunodeficiency.

Peculiarities of administration.

There is cross-allergenicity between other carbapenemes and beta-lactamic antibiotics, penicillins and cephalosporins. Before initiation meropenem therapy it is necessary to conduct careful interviewing as for previous history of hypersensitivity reactions to beta-lactamic antibiotics and use the preparation with caution in patients with such events in medical history. In case of development of allergic reaction to meropenem, the preparation should be discontinued and respective measures should be exercised.

In case when Ifeem is used in patients with liver disease, it is necessary to conduct close monitoring of transaminases and bilirubin levels.

Similar to other antimicrobial preparations, there is a possibility of overgrowth of insensitive to antibiotic microorganisms, that is why each patient should be continuously monitored.

Administration of the preparation for treatment infections caused by methicillin-resistant staphylococci is not recommended.

Similar to practically all antibiotics, during Ifeem therapy there have been seldom reports on pseudomembranous colitis, with the degree of severity from mild to life-threatening. That is why antibiotics should be indicated with caution in individuals with history of gastrointestinal complains, colitis in particular.

It is important to pay attention to the possibility of pseudomembranous colitis diagnosis in patients who developed diarrhea at Ifeem administration. Although investigations show that the toxin produced by Costridium difficile is one of the main reasons of colitis development that is associated with antibiotic use, other reasons should also be taken into consideration.

Caution should be exercised when Ifeem is administrated with potentially nephrotoxic preparations.

The ability to influence the reaction time when driving and working with other mechanisms

There is no data; however, no influence of Ifeem is expected to the ability of driving or working with mechanisms.

Interaction with other drugs and other forms of interaction.

Caution should be exercised when indicating Ifeem concomitantly with potentially nephrotoxic preparations.

Probenecid competes with meropenem as for tubular excretion and, thus, inhibits renal secretion, which leads to prolongation of half-decay period and increased plasma concentration of meropenem. As activity and term of action of Ifeem introduced without probenecid are identical, it is not recommended to administrate probenecid and Ifeem concomitantly.

Potential influence of Ifeem on protein binding with other preparations or their metabolism has not been studied.

Ifeem may decrease serum concentrations of valproic acid. In some patients these levels may reach subtherapeutical ones.

Ifeem has been indicated concomitantly with other medicinal preparations without any undesirable pharmacological action (except probenecid mentioned above).

Pharmacological properties.

Pharmacodynamics.

Ifeem is effective both as monotherapy and in combination with other antimicrobial ganets for treatment of polymicrobial infections.

Meropenem is an antibiotic of carbapeneme class intended for parenteral administration, which is stable to human dehydropeptidase-1 proteins. Meropenem has bactericidal action due to influence of bacterial cell wall synthesis. Easiness of meropenem crossing bacterial cell wall, high level of stability to most beta-lactamases and significant affinity to proteins binding penicillin (PBS) explain the powerful bactericidal action of meropenem against rather broad spectrum of aerobic and anaerobic bacteria.

Bactericidal concentrations are usually similar to minimal inhibiting concentrations.

Meropenem is stable in sensitivity tests, and these tests may be done under normal routine conditions. Tests in vitro demonstrate that meropenem acts synergistically with various antibiotics.

It has been proved both in vitro and in vivo, that meropenem has post-antibiotic effect.

Antibacterial spectrum of meropenem, which is established in vitro, includes the majority of clinically significant gram-positive and gram-negative, aerobic and anaerobic types of bacteria, namely:

Gram-positive aerobes

Bacillus spp., Corynebacterium diphtheriae, Enterococcus liquifaciens, Enterococcus avium, Listeria monocytogenes, Lactobacillus spp., Nocardia asteroides, Staphylococcus aureus (penicillinase-negative and positive), staphylococcus-coagulase-negative, including Staphylococcus saprophyticus, Staphylococcus capitis, Staphylococcus cohnii, Staphylococcus xylosus, Staphylococcus warneri, Staphylococcus hominis, Staphylococcus simulans, Staphylococcus intermedius, Staphylococcus sciuri, Staphylococcus lugdunensis, Streptococcus pneumoniae (sensitive and stable to penicillin), Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus equi, Streptococcus bovis, Streptococcus mitis, Streptococcus sanguis, Streptococcus viridans, Streptococcus salivarius, Streptococcus morbillorum, streptococcus G, streptococcus F,Rhodococcus equi.

Gram-negative aerobes

Achromobacter xylosoxidans, Acinetobacter anitratus, Acinetobacter lwoffii, Acinetobacter baumannii, Aeromonas hydrophila, Aeromonas sorbria, Aeromonas caviae, Alcaligenes faecalis, Bordetella bronchiseptica, Brucella melitensis, Campylobacter coli, Camylobacter jejuni, Citrobacter freundii, Citrobacter diversus, Citrobacter koseri, Citrobacter amalonaticus, Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter cloacae. Enterobacter sakazakii, Escherichia coli, Escherichia hermannii, Gardnerella vaginalis, Haemophilis influenzae (including positive to beta-lactamases and ampicillin-resistant strains), Haemophilus parainfluenzae, Haemophilus ducreyi, Helicobacter pylori, Neisseria meningitidis, Neisseria gonorrhoeae (including positive to beta-lactamases and stable to penicillin and spectinomycin 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, Burkholderia (Pseudomonas) cepacia, Pseudomonas fluorescens, Pseudomonas stutzeri, Pseudomonas pseudomallei, Pseudomonas acidovorans, Salmonella spp., including Salmonella enteridis/typhi, Serratia marcescens, Serratia liquifaciens, Serratia rubidaea, Shigella sonnei, Shigella flexneri, Shigella boydii, Shigella dysenteriae, Vibrio cholerae, Vibrio parahaemolyticus, Vibrio vulnificus, Yersinia enterocolitica.

Anaerobic bacteria

Actinomyces adontolyticus, Actinomyces meyeri, Bacteroides-Prevotella-Porphyromonasspp., Bacteroides fragilis, Bacteroides vulgatus, Bacteroides vorabilis, Bacteroides pneumosintes, Bacteroides coagulans, Bacteroides uniformis, Bacteroides distasonis. Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides eggerthii, Bacteroides capsillosis, Bacteroides buccalis, Bacteroides corporis, Bacteroides gracilis, Prevotella melaninogenica, Prevotella intermedia, Prevotella bivia, Prevotella splanchnicus, Prevotella oralis, Prevotella disiens, Prevotella rumenicola, Prevotella ureolyticus, Prevotella oris, Prevotella buccae, Prevotella denticola, Bacteroides levii, Porphyromonas asaccharoytica, 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, Peptostreptococcus asaccharolyticus, Peptostreptococcus magnus, Peptostreptococcus prevotii, Propionibacterium acnes, Propionibacterium avidum, Propionibacterium granulosum.

Xanthomonas maltophilia, Enterococcus faecium and susceptible to methicillinStreptococcus turned to be stable to meropenem.

 

Pharmacokinetics.

Intravenous 30-minute infusion of one dose of meropenem to healthy volunteers leads to maximal plasma concentration, which is 49 µg/ml for a dose of 1 g.

However, there is no absolute pharmacokinetic dependency between introduced and maximal concentration or area under curve. Moreover, there has been observed decrease of plasma clearance from 287 to 205 L/min at dose increase from 250 mg to 2 g.

Intravenous 5-minute bolus injection of one dose of the preparation to healthy volunteers leads to maximal plasma concentration, which is approximately 112 µg/ml for a dose of 1 g.

In 6 hours after intravenous introduction 500 mg of the preparation, the level of meropenem in plasma decreases to 1 µg/ml and less. At introduction of multiple doses with 8-hour intervals in patients with normal renal function, no meropenem accumulation occurs.

In patients with normal renal function half-life is approximately 1 hour. Plasma protein binding is approximately 2 %.

Approximately 70 % of intravenous dose is excreted with urine in unchanged state for 12 hours; further excretion with urine is insignificant. Concentration of meropenem in urine, which exceeds 10 µg/ml, is maintained for 5 hours after introduction of 500 mg dose. At introduction regime of 1 g every 6 hours no meropenem accumulation in plasma or urine has been observed.

The only meropenem metabolite is microbiologically inactive.

Meropenem penetrates well into most fluids and tissues of the organism, including cerebrospinal fluid of bacterial meningitis patients reaching the concentration that exceeds the one necessary for inhibiting of most bacteria.

Investigations in children have demonstrated that pharmacokinetics of meropenem in children is similar to the one in adults. The half-life of meropenem in children aged under 2 years is approximately 1.5-2.3 hours; linear pharmacokinetics is observed in the dose range of 10-40 mg/kg.

Pharmacokinetic studies in patients with renal failure have demonstrated that meropenem clearance correlates with creatinine clearance. In such patients dose adjustment is necessary.

Pharmacokinetic studies in elderly patients have demonstrated decrease of meropenem clearance, which correlated with age dependant decrease of creatinine clearance.

Pharmacokinetic studies in patients with liver diseases have demonstrated that the latter do not affect pharmacokinetics of meropenem.

Pharmaceutical characteristics.

Main physical and chemical properties: crystalline powder of white or yellowish color.

Incompatibility.

Ifeem cannot be mixed with other medicinal preparations. Use only recommended solvents (see Section “Way of introduction and doses”).

Shelf life: 3 years.

Storage conditions.

Store at temperature below 30ºC in the original package.

Keep out of the reach of children.

It is recommended to use immediately fresh solutions of the preparation for intravenous injections or intravenous introduction.

Prepared solutions of the preparation maintain stable at room temperature (up to 25 °С) or when cooled (4 °С). The data as for conditions and term of storage of meropenem solutions is provided in the table below: 

Solvent	Duration (hours) of stability at temperature up to
	25 оС	4 оС
Solutions (1-20 mg/ml) prepared with:
0.9 % sodium chloride	8	48
5 % glucose	3	14
5 % glucose and 0.225 % sodium chloride	3	14
5 % glucose and 0.9 % sodium chloride	3	14
5 % glucose and 0.15 % potassium chloride	3	14
2.5 % or 10 % mannitol solution for IV infusions	3	14
10 % glucose	2	8
5 % glucose and 0.02 % sodium bicarbonate for intravenous injections	2	8

Solutions of the preparation cannot be freezed.

Shake the obtained solution before use.

All vials are intended for one-time use only.

Standard aseptic means should be used during preparation and introduction.

Packing. Powder in a vial; 1 vial in a carton.

Manufacturer. Marksans Pharma Ltd.

Location.

Legal address

21 st Floor, Lotus Business Park, Off New Link Road, Andheri (West), Mumbai – 400053,India;

Manufacturing site address

Village Thana, Baddi, Solan, Himachal Pradesh – 173205, India.

Applicant. Ananta Medicare Ltd.

Location.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, Great Britain.

Category of dispensing. On prescription.

The date of the last review. 23.07.2012.