Dosage form Imipenem with cilastatin: powder for solution for intramuscular injection. Imipenem Cilastatin: instructions for use, warnings and reviews Imipenem Cilastatin trade name

Imipenem cilastatin is a beta-lactam antibacterial agent (antibiotic) that is part of the carbapenem group. The drug acts on many pathogenic bacteria. Consider the cases in which Imipenem cilastatin is prescribed, and how to use it.

Drug properties

Imipenem cilastatin is effective in infection with many microorganisms, including those resistant to antibiotics from the groups of aminoglycosides, cephalosporins, penicillins. Pharmacological properties - antibacterial, bactericidal, antimicrobial.

The active substance is a derivative of thienamycin. When it enters the body, it inhibits the synthesis of cells of pathogenic bacteria. The spectrum of action includes the entire list of microorganisms of clinical significance.

The second component does not show an antibacterial effect, but inhibits the enzyme that oxidizes imipenem. This increases the amount of active substance in the kidneys. The bioavailability of the agent (the ability to be absorbed by the body) is 75-95%.

The medicine is released in the form of a powder, from which it is necessary to prepare a solution. 1 bottle contains 500 mg of each of the 2 main components. The trade name of the drug is "Imipenem with cilastatin."

Indications for appointment

In accordance with the instructions for use of Imipenem, cilastatin is prescribed for infectious and inflammatory diseases.

Indications for droppers (intravenous administration) are severe infections:

urinary tract;
Skeletal system;
Skin, subcutaneous tissue.

Droppers are also prescribed for gynecological, intra-abdominal infections, septicemia, endocarditis.

Indications for injections - infectious diseases of mild, moderate severity:

Skin, subcutaneous tissues;
Gynecological;
Intra-abdominal.

Imipenem cilastatin is also used in the period after surgery to prevent infection.

Method of use, doses

Imipenem cilastatin is used as a dropper or administered intramuscularly. If droppers are prescribed, the daily amount for adults, children from 12 years old will be 1-4 g. kg.

The daily amount for intramuscular injection is 1-1.5 g. This dose is administered in 2 divided doses. The largest allowable amount for drip administration for adults is 4 g / day, for children - 2 g / day, for intramuscular injections - 1.5 g / day. (for adults). Clinical studies of intramuscular administration of the drug to children have not been conducted.

Therapy of patients older than 65 years is carried out with caution. For this purpose, the minimum allowable doses that exhibit a therapeutic effect are selected. It is mandatory to monitor the work of the kidneys.

Procedure duration:

20-30 min. for a solution volume of 250-500 mg;
40-60 min. for volumes over 500 mg.

If nausea occurs, the speed of the dropper is reduced. Intramuscular injections are made into a large muscle (deeply). After eliminating the manifestations of the disease, the drug is used for another 2 days.

How to make a drip solution

Pour the solvent into the bottle with the powder (dextrose solution 5% or 10%, NaCl solution 0.9%, etc.) in the amount of 10-20 ml;
Shake vigorously to obtain a suspension;
Transfer it to a container with a solvent, you should get 100 ml of the volume of the solution;
If there is a little medicine left on the walls of the vial, add 20 ml of the solution obtained earlier and shake vigorously;
Combine both mixtures and stir.

The resulting solution should become clear. 100 ml contains 5 mg/ml of the active substance. The antibiotic, ready for use, is stored at room temperature (up to 4 hours) or in the refrigerator (up to 24 hours).

How to prepare an injection solution

Enter the solvent (injection water, NaCl 0.9%, lidocaine 1%) into the vial with the powder in an amount of 2 ml.
Shake vigorously until a suspension (white or slightly yellow) is obtained.

Side effects

Imipenem cilastatin can adversely affect various organs and systems, causing various kinds of symptoms.

Contraindications to the appointment

Instructions for use Imipenem cilastatin provides for the following contraindications:

With caution, Imipenem cilastatin is prescribed for:

Diseases of the central nervous system;
Colitis pseudomembranous;
Lesions of the gastrointestinal tract in the history of the disease;
Creatinine clearance (CC) up to 70 ml / min / 1.73 m?;
Taking valproic acid.

In addition, the drug is used with caution in nursing mothers, patients on hemodialysis, as well as in the elderly.

special instructions

An antibiotic prepared for droppers is not used for injections, and vice versa. Imipenem cilastatin should not be used to treat meningitis. Before use, find out if the patient is allergic to beta-lactam agents.

In the elderly, as a rule, there is renal dysfunction, therefore, dose adjustment may be required downwards.

To avoid negative effects from the CNS in patients with convulsions, TBI (traumatic brain injury), it is necessary to take antiepileptic drugs during the entire period of using Imipenem with cilastatin. There is no information on drug overdose.

Interaction with other drugs

Imipenem cilastatin is contraindicated to prescribe with other antibacterial agents, preparations containing salts of lactic acid. If it is used with Ganciclovir, convulsions may develop.

When used with penicillin antibiotics, cephalosporins, there is a high risk of cross-allergy. In relation to other beta-lactam drugs (monobactams, cephalosporins, penicillins), Imipenem cilastatin is an antagonist, i.e., weakens their action.

The accumulation of imipenem in the urine leads to a combination of the drug with Cisplatin, which is an inhibitor of the enzyme dehydropeptidase.

Analogues, price

Analogues of the drug Imipenem cilastatin are: Tienam, Aquapenem, Tiepenem, Cilapenem, Imipenem cilastatin Jodas, Imipenem cilastatin Spencer, Grimipenem. It is sold by prescription. The price of the drug Imipenem cilastatin - from 450 rubles. for 1 bottle. Store the medicine at temperatures up to 25 ° C, in a dark place.

The advantage of the tool is its high efficiency in relation to a wide range of microorganisms. This is very important in cases where it is necessary to treat patients who are in serious or critical condition.

Imipenem cilastatin effectively suppresses the symptoms of infectious diseases of unknown etiology, sometimes its use is the only chance to exclude a lethal outcome.

Among the shortcomings can be noted the high cost, which significantly limits the use of the drug.

Description

Powder from white to pale yellow.

Composition for 1 bottle

dosage 250 mg/250 mg

250 mg Imipenem/250 mg Cilastatin and sodium bicarbonate

dosage 500 mg/500 mg

500 mg Imipenem/500 mg Cilastatin and sodium bicarbonate

Pharmacotherapeutic group

Antibiotic of the carbapenem group.

ATX code: J01DH51.

Pharmacological properties

Pharmacodynamics

Imicinem-TF is a broad-spectrum antibiotic consisting of two components.

Imipenem inhibits bacterial cell wall synthesis and has a bactericidal effect against a wide range of gram-positive and gram-negative pathogens, aerobic and anaerobic.

Cilastatin sodium inhibits dehydropeptidase, an enzyme that metabolizes imipenem in the kidneys, which significantly increases the concentration of unchanged imipenem in the urinary tract. Cilastatin does not have its own antibacterial activity, does not inhibit bacterial beta-lactamase.

The antimicrobial spectrum of Imicinem-TF includes virtually all clinically significant pathogens. In vitro antibiotic active against aerobic gram-negative bacteria: Achromobacter spp., Acinetobacter spp. (formerly Mima-Herellea), Aeromonas hydrophila, Alcaligenes spp., Bordetella bronchicanis, Bordetella bronchiseptica, Bordetella pertussis, Brucella melitensis, Campylobacter spp., Capnocytophaga spp., Citrobacter spp. (including Citrobacter diversus, Citrobacter freundii), Eikenella corrodens, Enterobacter spp. (including Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter cloacae), Escherichia coli, Gardnerella vaginalis, Haemophilus influenzae (including beta-lactamase producing strains), Haemophilus ducreyi, Haemophilus parainfluenzae, Hafnia alvei, Klebsiella spp. (including Klebsiella oxytoca, Klebsiella pneumoniae, Klebsiella ozaenae), Moraxella spp., Morganella morganii (formerly Proteus morganii), Neisseria gonorrhoeae (including strains that produce penicillinase), Neisseria meningitidis, Pasteurella multocida, Proteus spp. (including Proteus mirabilis, Proteus vulgaris), Plesiomonas shigelloides, Providencia spp. (including Providencia rettgeri /formerly Proteus rettgeri/, Providencia stuartii), Pseudomonas spp. (including Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas pseudomallei, Pseudomonas putida, Pseudomonas stutzeri), Salmonella spp. (including Salmonella typhi), Serratia spp. (including Serratia proteamaculans /formerly Serratia liquefaciens/, Serratia marcescens), Shigella spp., Yersinia spp. (including Yersinia enterocolitica, Yersinia pseudotuberculosis); aerobic gram-positive bacteria: Bacillus spp. Enterococcus faecalis Erysipelothrix rhusiopathiae Listeria monocytogenes Nocardia spp. Pediococcus spp. group B (including Streptococcus agalactiae), Streptococcus spp. groups C, G, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus viridans (including hemolytic alpha and gamma strains); anaerobic Gram-negative bacteria: Bacteroides spp., Bacteroides distasonis, Bacteroides fragilis, Bacteroides ovatus, Bacteroides thetaomicron, Bacteroides uniformis, Bacteroides vulgatus, Bilophila wadsworthia, Fusobacterium spp., Fusobacterium necrophorum, Fusobacterium nucleatum, Porphyromonas asaccharolytica (formerly Bacteroides asaccharolytica), Prevotella bivia (formerly Bacteroides bivius) , Prevotella disiens (formerly Bacteroides disiens), Prevotella intermedia (formerly Bacteroides intermedius), Prevotella melaninogenica (formerly Bacteroides melaninogenicus), Veillonella spp.; anaerobic gram-positive bacteria: Actinomyces spp., Bifidobacterium spp., Clostridium spp. (including Clostridium perfringens), Eubacterium spp., Lactobaccilus spp., Mobilincus spp., Microaerophilic streptococcus, Peptococcus spp., Peptostreptococcus spp., Propionibacterium spp. (including Propionibacterium acnes); others: Mycobacterium fortuitum, Mycobacterium smegmatis.

To Imitsinem-TF resistant Xanthomonas maltophilia (formerly Pseudomonas maltophilia) and some strains of Pseudomonas cepacia, as well as Streptococcus faecium and methicillin-resistant staphylococci.

In vitro tests show that the antibiotic acts synergistically with antibiotics from the aminoglycoside group against certain isolates of Pseudomonas aeruginosa.

Imicinem-TF is effective as monotherapy or in combination with other antimicrobial agents in the treatment of polymicrobial infections.

Pharmacokinetics

Distribution

After intravenous administration, the bioavailability of imipenem is 98%. The antibiotic is well distributed, creating high concentrations in various tissues and body fluids. Plasma protein binding is 20%.

Metabolism and excretion

Imipenem is metabolized in the kidneys by hydrolysis of the beta-lactam ring by renal dehydropeptidase. The half-life of imipenem is 1 hour.

Pharmacokineticsin special clinical situations

In case of impaired renal function, as well as in the elderly (over 65 years), there is a decrease in total and renal clearance and an increase in the half-life of imipenem.

Indications for use

Polymicrobial and mixed aerobic-anaerobic infections, empiric therapy prior to identification of pathogens.

Infections caused by drug-sensitive strains of microorganisms: pneumonia (including nosocomial infections), urinary tract infections, abdominal infections, gynecological infections, skin and soft tissue infections, septicemia, bone and joint infections, infective endocarditis, mixed infections.

Before using the drug in pediatric patients, it is necessary to study the information provided in the sections "Precautions" and "Method of application and dosage".

Contraindications

Hypersensitivity to any of the components of the drug. Hypersensitivity to carbapenems, penicillins or other beta-lactam antibiotics, children under 3 months of age.

WITH caution Imicinem-TF should be given concomitantly with potentially nephrotoxic drugs, as well as in patients with dyspeptic symptoms, especially associated with colitis, and in elderly patients.

Precautionary measures

Use during pregnancy and lactation

Clinical safety of Imicinem-TF during pregnancy not installed. Therefore, Imicinem-TF should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. In each case, the drug must be used under the direct supervision of a physician.

If necessary, the use of Imicinem-TF during lactation consideration should be given to stopping breastfeeding.

special instructions

Imicinem-TF is not indicated for the treatment of meningitis because safety and efficacy have not been established. If meningitis is suspected, appropriate antibiotics should be given.

Patients on hemodialysis, especially with diseases of the central nervous system, Imicinem-TF can be prescribed only in cases where the expected benefit of therapy outweighs the potential risk of worsening renal failure.

During the treatment of infections caused by Pseudomonas aeruginosa, it is recommended to conduct periodic antibiotic sensitivity tests according to the clinical situation.

In order to prevent the development of resistance and maintain the effectiveness of Imicinem-TF, the medicinal product should only be used to treat or prevent infections caused by proven (or suspected) microorganisms susceptible to imipenem. In the absence of information on an identified pathogen and its susceptibility, the empirical choice of an antibiotic should be made on the basis of local epidemiological and microbial susceptibility data.

Pediatric use

Imicinem-TF can be used to treat children with sepsis. The use of the drug in children under the age of 3 months, as well as in children with impaired renal function, has not been studied enough.

Method of application and dosage

The average daily dose of Imicinem-TF is determined depending on the severity of the infection and is divided into several equal doses, taking into account the degree of sensitivity of microorganisms, kidney function and body weight.

For adults the average therapeutic dose for intravenous infusion is 1-2 g / day (in terms of imipenem), divided into 3-4 infusions. The maximum daily dose is 4 g.

Table 1

Imicinem-TF at doses ≤500 mg should be administered intravenously over 20-30 minutes, at doses >500 mg - over 40-60 minutes. Patients who experience nausea during infusion should reduce the rate of administration.

For prevention of postoperative infections the drug should be administered intravenously at a dose of 1 g during induction anesthesia and at a dose of 1 g after 3 hours. In the case of high-risk surgery, an additional 500 mg should be administered 8 and 16 hours after anesthesia.

Doses of Imicinem-TF for IV infusion patients with dysfunctionkidney function andweighing 70 kg or more are presented in table 2.

Imicinem-TF should not be used in patients with creatinine clearance less than 5 ml/min/1.73 m2 unless hemodialysis is scheduled every 48 hours. Both imipenem and cilastatin are cleared from the circulation during hemodialysis. Imicinem-TF should be administered after a hemodialysis session and at 12-hour intervals from the end of the procedure.

table 2

Daily dose based on the severity of the infection*	Recalculation of the daily dose depending on the QC (ml / min / 1.73 m2)
	41-70	21-40	6-20
1 g	250 mg every 8 hours or 250 mg every 12 hours \| 250 mg every 12 hours	250 mg every 12 hours	250 mg every 12 hours
1.5 ggg4 g	250 mg every 6 hours 250 mg every 8 hours 500 mg every 8 hours 250 mg every 6 hours	250 mg every 8 hours	250 mg every 12 hours 250 mg every 12 hours
2 g	500 mg every 8 hours	250 mg every 6 hours	250 mg every 12 hours
3 g	500 mg every 6 hours	500 mg every 8 hours	500 mg every 12 hours
4 g	750 mg every 8 hours	500 mg every 6 hours	500 mg every 12 hours

* see Table 1.

Children older than 3 months weighing less than 40 kg the drug is prescribed at a dose of 15-25 mg / kg / dose every 6 hours. Based on studies in adults, the maximum daily dose for the treatment of infections caused by fully susceptible microorganisms is 2.0 g per day, infections with moderate susceptibility of microorganisms (in primarily caused by some strains of P. aeruginosa) is 4.0 g/day. Higher doses (up to 90 mg/kg/day in older children) may be used in patients with cystic fibrosis. Medicine not recommended for use in children with CNS infections due to the risk of seizures and in children with body weight, as there are no data on the safety of use.

Rules for the preparation and administration of the solution

Imicinem-TF should be administered intravenously as an infusion.

To prepare a solution for in/vintroductions the contents of the vial are pre-dissolved in 10 ml of one of the following infusion solutions: 0.9% sodium chloride solution, 5%, 10% dextrose aqueous solution, 5% and 10% mannitol solution.

The resulting suspension must not be used for direct administration!

The suspension is shaken well and transferred into a vial or container with the rest of the infusion solution (140 ml). The total volume of the solution is 150 ml. To ensure complete transfer of the contents of the vial, the above procedure must be repeated by adding again 10 ml of the resulting solution to the vial, and after shaking, transfer to the vial or container with the rest of the solution. The resulting solution (150 ml) is shaken until a clear liquid is formed. To prepare a solutionImicinema-TFdo not use solvents containing lactic acid salt (lactate)!

Side effect

Local reactions: with a / in the introduction - erythema, pain and infiltrates at the injection site of the drug, thrombophlebitis.

Allergic reactions: rash, itching, urticaria, fever, anaphylactic reactions, erythema multiforme, angioedema; rarely - exfoliative dermatitis, toxic epidermal necrolysis.

Soaspects of the digestive system: nausea, vomiting, diarrhea; a moderate increase in the activity of transaminases, bilirubin and / or serum alkaline phosphatase, tooth staining; rarely - pseudomembranous colitis, hepatitis.

From the side of laboratory indicators: eosinophilia, leukopenia, neutropenia (including agranulocytosis), thrombocytopenia, thrombocytosis, decreased hemoglobin levels. In some cases, a direct positive Coombs test was noted.

From the sideurinarysystems: there was an increase in serum creatinine and urea nitrogen levels; rarely - oliguria / anuria, polyuria, acute renal failure. There have been cases of discoloration of urine (this phenomenon is safe and should not be confused with hematuria).

From the side of the central nervous system and peripheral nervous system: when prescribing intravenous infusions of Imicinem-TF (as in the treatment of other antibiotics of the beta-lactam group), cases of myoclonus, mental disorders, including hallucinations, confusion, epileptic seizures, paresthesia, and taste disturbances are described.

Side effects rarely require discontinuation of therapy and are usually mild and transient; severe side effects are rare.

Overdose

Symptoms: increased severity of side effects.

Treatment: the drug should be discontinued or its dose reduced. Carry out symptomatic therapy. It is possible to remove Imicinem-TF by hemodialysis, however, the effectiveness of this procedure in case of overdose has been little studied.

Interaction with other drugs

Pharmaceutical interaction

Imicinem-TF solutions should not be mixed or administered simultaneously with other antimicrobial drugs. Imicinem-TF is chemically incompatible with a lactic acid salt (lactate), therefore, when preparing drug solutions, solvents containing a lactic acid salt should not be used.

With simultaneous use with penicillins, cephalosporins and other beta-lactam antibiotics, cross-allergy is possible.

Terms and conditions of storage

Store in a place protected from moisture and light at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life 2 years. Do not use after the expiry date stated on the package.

Terms of dispensing from pharmacies

The drug is dispensed by prescription.

Package

250 mg/250 mg or 500 mg/500 mg in a 10 ml vial.

5 bottles in a pack or 36 bottles in a box (packaging for hospitals).

Company manufacturer

JLLC "TripleFarm", st. Minskaya, 2B, 223141, Logoisk, Republic of Belarus, tel./fax: (+375) 1774 43 181, e-mail: .

Imipenem inhibits bacterial cell wall synthesis. Imipenem has a bactericidal effect against a wide range of pathogenic aerobic and anaerobic gram-negative and gram-positive microorganisms. Imipenem is resistant to cleavage by bacterial beta-lactamases, including cephalosporinase and penicillinase secreted by gram-negative and gram-positive bacteria, which ensures its effectiveness. A feature of imipenem is the preservation of high activity against groups of microorganisms insensitive to other antibiotics. Microorganisms susceptible to imipenem: gram-positive aerobes - Staphylococcus aureus (including penicillinase-producing strains), Enterococcus faecalis, Staphylococcus epidermidis (including penicillinase-producing strains), Streptococcus pneumoniae, Streptococcus agalactiae (group B streptococci), Streptococcus pyogenes, Bacillus spp., Listeria monocytogenes, Nocardia spp., Staphylococcus saprophyticus, Green streptococci (Viridans group), Group C and G streptococci; gram-negative aerobes - Citrobacter spp., Enterobacter spp., Acinetobacter spp., Gardnerella vaginalis, Escherichia coli, Klebsiella spp., Haemophilus parainfluenzae, Haemophilus influenzae, Proteus vulgaris, Pseudomonas aeruginosa, Providencia rettgeri, Morganella morganii, Serratia spp. (including Serratia marcescens), Aeromonas hydrophila, Capnocytophaga spp., Alcaligenes spp., Neisseria gonorrhoeae (including penicillinase-producing strains), Haemophilus ducreyi, Providencia stuartii, Pasteurella spp.; gram-positive anaerobes - Eubacterium spp., Clostridium spp., Bifidobacterium spp., Peptostreptococcus spp., Peptococcus spp., Propionibacterium spp.; gram-negative anaerobes - Fusobacterium spp., Bacteroides spp. (including Bacteroides fragilis), Prevotella melaninogenica, Prevotella disiens, VeiIlonella spp., Prevotella bivia. Imipenem is not active against Mycoplasma spp., Chlamydia trachomatis, Enterococcus faecium, some strains of P. cepacia, Xanthomonas (Pseudomonas) maltophilia, methicillin-resistant staphylococci, fungi, viruses.
After intravenous administration of 500 mg of imipenem, the maximum plasma concentration is from 21 to 58 μg / ml and is reached after 20 minutes. The maximum concentration of imipenem decreases to a value of 1 μg / ml and below within 4-6 hours after administration. With intramuscular injection, bioavailability is 95%. The elimination half-life of imipenem is 1 hour. It binds to plasma proteins by 20%. Approximately 70% of intravenously administered imipenem is excreted by the kidneys within 10 hours. The concentration of imipenem in the urine of more than 10 mcg / ml can persist for 8 hours after intravenous administration of the drug. Imipenem is metabolized in the kidneys by the action of renal dehydropeptidase by hydrolysis of the beta-lactam ring. Imipenem is rapidly and widely distributed into most tissues and body fluids. Imipenem after administration was determined in the vitreous body of the eyeball, intraocular fluid, lung tissue, sputum, pleural fluid, peritoneal fluid, bile, cerebrospinal fluid, endometrium, fallopian tubes, myometrium, bone tissue, interstitial fluid, skin, connective tissue and other tissues and organs . Imipenem is eliminated from the body by hemodialysis.

Indications

Lower respiratory tract infections caused by Staphylococcus aureus (penicillinase-producing strains), Streptococcus pneumoniae, Enterobacter spp., Acinetobacter spp., Escherichia coli, Haemophilus parainfluenzae, Haemophilius influenza, Klebsiella spp., Serratia marcescens; intra-abdominal infections caused by Staphylococcus aureus (penicillinase-producing strains), Enterococcus faecalis, Staphylococcus epidermidis, Enterobacter spp., Citrobacter spp., Escherichia coli, Morganella morganii, Klebsiella spp, Proteus spp., Bifidobacterium spp., Pseudomonas aeruginos, Bacteroides spp. ., Clostridium spp., Peptococcus spp., Peptostreptococcus spp., Eubacterium spp., Propionibacterium spp., Bacteroides fragilis, Fusobacterium spp.; urinary tract infections caused by Staphylococcus aureus (penicillinase-producing strains), Enterococcus faecalis, Enterobacter spp., Klebsiella spp, Escherichia coli, Morganella morganii, Providencia rettgeri, Proteus vulgaris, Pseudomonas aeruginosa; gynecological infections caused by Enterococcus faecalis, Staphylococcus epidermidis, Staphylococcus aureus (penicillinase-producing strains), Escherichia coli, Enterobacter spp. spp., Peptococcus spp., Propionibacterium spp., Bacteroides spp., Bacteroides fragilis; bone and joint infections caused by Staphylococcus aureus (penicillinase-producing strains), Enterococcus faecalis, Enterobacter spp., Staphylococcus epidermidis, Pseudomonas aeruginosa; bacterial septicemia caused by Enterococcus faecalis, Streptococcus pneumoniae, Enterobacter spp., Staphylococcus aureus (penicillinase-producing strains), Escherichia coli, Serratia spp., Klebsiella spp, Bacteroides spp., Bacteroides fragilis, Pseudomonas aeruginosa; infective endocarditis, which is caused by Staphylococcus aureus (penicillinase-producing strains); skin and soft tissue infections caused by Enterococcus faecalis, Streptococcus pyogenes, Staphylococcus aureus (penicillinase-producing strains), Acinetobacter spp., Staphylococcus epidermidis, Citrobacter spp., Escherichia coli, Enterobacter spp., Klebsiella spp., Proteus vulgaris, Morganella morganii , Providencia rettgeri, Serratia spp., Pseudomonas aeruginosa, Peptococcus spp., Bacteroides spp., Peptostreptococcus spp., Bacteroides fragilis, Fusobacterium spp. ; prevention of postoperative infections in patients with a high risk of intraoperative infection during surgery and in patients at risk with a high probability of developing postoperative infectious complications.

Route of administration of imipenem and dosage

Imipenem is administered intravenously, intramuscularly. The dosage is set individually depending on the indications, tolerability of the drug, condition, age, body weight, kidney function of the patient.
In persons over 65 years of age, given the reduced functions of the liver, kidneys, cardiovascular system, characteristic of this age group, the presence of concomitant diseases and concomitant drug treatment, care must be taken when choosing a dose, adhering to the lower limits of the recommended doses. In these patients, monitoring of the excretory function of the kidneys is recommended.
Intravenous imipenem is preferred for initial treatment of bacterial sepsis, endocarditis, and other severe or life-threatening infections (including Pseudomonas aeruginosa lower respiratory tract infections), and for significant physiological impairment (eg, shock).
Against the background of imipenem therapy, life-threatening conditions (convulsions, severe anaphylaxis, severe clinical forms of pseudomembranous colitis of clostridial etiology) may develop, which require special attention and the provision of emergency medical care.
During treatment with imipenem, Pseudomonas aeruginosa can quickly develop resistance to the drug. Therefore, in the process of treating diseases that are caused by Pseudomonas aeruginosa, periodic antibiotic sensitivity tests should be carried out according to the clinical situation.
There is information about partial cross-allergy when using imipenem and other beta-lactam antibiotics (cephalosporins, penicillins). For many antibiotics of the beta-lactam group, the possibility of developing severe reactions (including anaphylaxis) has been reported with their use.
To prevent the development of resistance and maintain the effectiveness of imipenem, the drug should be used only for the treatment of those infections that are caused by susceptible (proven or suspected) microorganisms to imipenem. If there is information about the identified pathogen and its sensitivity to antibiotics, the doctor is guided by it to select the optimal antibiotic, and in the absence of this information, the empirical choice of an antibacterial agent is based on sensitivity data and on the basis of local epidemiological data.
If a patient develops diarrhea during treatment with imipenem, it is first necessary to exclude Clostridium difficile-associated diarrhea, which, under conditions of suppression of normal flora in the colon, is caused by an aggressive growth of the Clostridium difficile population with the accumulation of toxins A and B produced by the microorganism. Strains that are capable of increased production of toxins cause the most severe cases that are resistant to any antibiotic treatment and sometimes require colectomy. Perhaps the development of late cases (2 months after completion of treatment) of this complication. If Clostridium difficile-associated diarrhea is suspected or confirmed, imipenem may need to be discontinued with co-administration of treatment to maintain protein parameters, fluid and electrolyte balance, suppress Clostridium difficile infection, and consult a surgeon.
During treatment with imipenem, it is recommended to refrain from performing potentially dangerous activities that require increased attention and speed of psychomotor reactions (including driving vehicles).

Contraindications for use

Hypersensitivity (including to other beta-lactam antibiotics, cephalosporins, penicillins), children under 3 months (for intravenous administration; safety and efficacy have not been established) and up to 12 years (for intramuscular administration; safety and efficacy have not been established), children with impaired renal function (plasma creatinine more than 2 mg / dl), patients with creatinine clearance less than 5 ml / min / 1.73 m2 (for intravenous administration) and less than 20 ml / min / 1.73 m2 (for intramuscular administration), breastfeeding period.

Application restrictions

History of gastrointestinal disease, pseudomembranous colitis, central nervous system disease, patients with creatinine clearance less than 70 ml/min/1.73 m2 (for intravenous administration) and 20 to 70 ml/min/1.73 m2 ( for intramuscular injection), patients on hemodialysis, pregnancy.
Use during pregnancy and lactation
No studies have been conducted on the use of imipenem in pregnant women. Imipenem should be used during pregnancy only when the expected benefit to the mother outweighs the potential risk to the fetus. During therapy with imipenem, it is necessary to stop breastfeeding (imipenem is excreted in breast milk).

side effects of imipenem

Local reactions: pain at the injection site, phlebitis, thrombophlebitis, vein thickening at the injection site, erythema at the injection site, infection at the injection site.
Digestive system: nausea, vomiting, diarrhea, clostridial pseudomembranous colitis (including after completion of treatment), hepatitis (including fulminant), hemorrhagic colitis, liver failure, gastroenteritis, jaundice, glossitis, abdominal pain, hypertrophy of the papillae of the tongue, pigmentation of the teeth and tongue, pain in the throat, heartburn, hypersalivation, increased levels of serum transaminases, bilirubin, alkaline phosphatase, increased levels of low density lipoproteins.
Nervous system and sense organs: encephalopathy, confusion, tremor, myoclonus, vertigo, headache, paresthesia, mental disorders, hallucinations, tinnitus, hearing loss, taste perversion.
Respiratory system: shortness of breath, pain in the thoracic spine, chest discomfort, hyperventilation.
Cardiovascular system and blood: palpitations, tachycardia, inhibition of the function of the red germ of the bone marrow, pancytopenia, thrombocytopenia, neutropenia, leukopenia, hemolytic anemia, leukocytosis, eosinophilia, platelets, lymphocytosis, monocytosis, an increase in the number of basophils, agranulocytosis, a decrease in hemoglobin and hematocrit, an increase in prothrombin time, positive direct Coombs test.
Allergic reactions and skin: itching, rash, urticaria, cyanosis, hyperhidrosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, exfoliative dermatitis, erythema multiforme, fever, anaphylactic reactions.
Urogenital system: oliguria, polyuria, anuria, proteinuria, leukocyte-, erythrocyte-, cylindruria, increased bilirubin concentration and change in urine color, acute renal failure, increased serum creatinine and urea.
Others: candidiasis, increased plasma concentration of potassium, decreased serum concentrations of sodium and chlorine.

Interaction of imipenem with other substances

Cilastatin increases the concentration of unchanged imipenem in the urine and urinary tract by inhibiting its metabolism.
With the combined use of imipenem and ganciclovir, the development of generalized seizures is possible. These drugs should not be administered together, unless the expected benefit of treatment outweighs the possible risk.
The use of probenecid during therapy with imipenem is not recommended, as probenecid increases the plasma concentration and half-life of imipenem.
Imipenem reduces the plasma concentration of valproic acid, which is associated with a risk of increased seizure activity. During co-treatment with imipenem and valproic acid, monitoring of plasma concentrations of valproic acid is recommended.
Imipenem should not be mixed in the same syringe with other antibiotics.

Overdose

There is no data. In case of an overdose of imipenem, it is recommended to discontinue the drug, prescribe supportive and symptomatic treatment. Imipenem is eliminated by hemodialysis, but the effectiveness of this procedure in case of drug overdose is unknown.

Trade names of drugs with the active substance imipenem

Combined drugs:
Imipenem + Cilastatin: Aquapenem, Grimipenem®, Imipenem and Cilastatin, Imipenem and Cilastatin Jodas, Imipenem and Cilastatin Sodium, Imipenem and Cilastatin Spencer, Imipenem with Cilastatin, Imipenem + Cilastatin, Tienam, Tiepenem®, Cilapenem, Cilaspen.

Intravenously (in / in) drip. Dosage form for intravenous use should not be administered intramuscularly. The dosage recommendations for Imipenem + Cilastatin indicate the amount of imipenem to be administered. The calculation of the total daily dose should be based on the severity of the infection and should be spread over several applications in equal doses, taking into account the degree of sensitivity of one or more pathogens, kidney function and body weight of the patient. It is especially important to reduce the dose depending on body weight in those patients whose weight is significantly below 70 kg and / or there is moderate or severe renal insufficiency. The average therapeutic daily dose is 1-2 g of imipenem divided into 3-4 applications. For the treatment of moderate infections, the drug can also be used at a dose of 1 g twice a day. In the case of infections caused by less sensitive microorganisms, the daily dose of the drug for intravenous infusion may be increased to a maximum of 4 g (imipenem) per day or 50 mg/kg per day, whichever is the lower dose. Each dose of Imipenem + Cilastatin less than or equal to 500 mg should be administered intravenously over 20-30 minutes. Each dose over 500 mg should be administered intravenously over 40-60 minutes. Patients who experience nausea during the infusion should slow down the rate of administration of the drug. Due to the high antimicrobial activity of Imipenem + Cilastatin, it is recommended that its total daily dose not exceed 50 mg/kg or 4 g (imipenem)/day, whichever is the lower dose. Although patients with cystic fibrosis with normal renal function were treated with Imipenem + Cilastatin at doses up to 90 mg/kg per day divided into several doses, the total dose did not exceed 4 g (imipenem) per day. Imipenem + Cilastatin has been successfully used as monotherapy in immunocompromised cancer patients for confirmed or suspected infections such as sepsis. To adjust the dose of the drug in the treatment of adult patients with impaired renal function, it is necessary: Based on the characteristics of the infection, choose the total daily dose of the drug. Select the appropriate reduced dose of the drug, based on the daily dose and creatinine clearance of the patient. Select in the left column the body weight closest to the patient's body weight (kg). With the introduction of a dose of 500 mg in patients with a creatinine clearance of 6-20 ml / min / 1.73 m2, an increase in the risk of seizures is possible. Imipenem + Cilastatin should not be administered intravenously to patients with creatinine clearance less than 5 ml/min/1.73 m2 unless hemodialysis is performed no later than 48 hours after infusion. When treating patients with CC less than 5 ml / min / 1.73 m2 on hemodialysis, recommendations on the dosing regimen for patients with CC 6-20 ml / min / 1.73 m2 should be applied. Both imipenem and cilastatin are cleared from the circulatory system during hemodialysis. In this regard, the drug Imipenem + Cilastatin should be administered to patients after hemodialysis and then at 12-hour intervals from the end of the procedure. Patients on hemodialysis, especially if they have diseases of the central nervous system, should be closely monitored; the appointment of the drug Imipenem + Cilastatin in patients undergoing hemodialysis is recommended only in cases where the benefit of treatment outweighs the potential risk of seizures. There are currently insufficient data to recommend Imipenem + Cilastatin in patients on peritoneal dialysis. The state of the kidneys in elderly patients cannot be fully determined only on the basis of measuring the level of residual blood nitrogen or creatinine. For the selection of dosages in such patients, it is recommended to determine the creatinine clearance. For elderly patients with normal renal function, dose adjustment is not required. For patients with impaired liver function, dose adjustment is not required. For the prevention of postoperative infections in adults, Imipenem + Cilastatin should be administered at a dose of 1 g at the induction of anesthesia and then 1 g after 3 hours. In the case of high-risk surgery (for example, during operations on the colon and rectum), two additional doses of 500 mg should be administered 8 and 16 hours after induction of anesthesia. Dosing regimen in children from 3 months of age For children, the following dosing regimen is recommended: Children weighing >40 kg should receive the same doses as adult patients. Children older than 3 months weighing less than 40 kg should receive the drug at a dose of 15 mg / kg at 6-hour intervals. The maximum daily dose should not exceed 2 g. Imipenem + Cilastatin is not recommended for the treatment of meningitis. If meningitis is suspected, appropriate antibiotics should be given. Rules for preparing the solution: The drug must not be mixed or added to other antibiotics. The drug is pharmaceutically incompatible with lactic acid (lactate) and should not be prepared on the basis of solvents containing it. However, intravenously, the drug can be administered through the same infusion system as the solution containing lactate. The following solvents are used to prepare the infusion solution: 5% dextrose solution, 10% dextrose solution, 5% dextrose solution and 0.9% sodium chloride solution, 5% dextrose solution and 0.45% sodium chloride solution, 5% dextrose solution and 0.225 % sodium chloride solution, 5% dextrose solution and 0.15% potassium chloride solution, mannitol 5% and 10%, in the ratio of 500 mg of imipenem per 100 ml of solvent. The contents of the vial must first be dissolved. To do this, 10 ml of a suitable solvent should be transferred with a syringe into a vial with the drug. The resulting solution can not be used for injection! After dilution, the vial is shaken well, and then the contents are transferred to a vial or container with the remainder of the solvent (90 ml). The total solvent volume is 100 ml. For complete transfer of the drug (residues of the drug on the walls of the vial), 10 ml of the previously obtained solution is added to the same vial, shaken well and transferred again to the vial or container with the already obtained solution. Only then is the solution ready for use. The concentration of imipenem in the resulting solution is 5 mg/ml.

INN: Imipenem, Cilastatin

Manufacturer: Himfarm JSC

Anatomical-therapeutic-chemical classification: Imipenem in combination with beta-lactamase inhibitors

Registration number in the Republic of Kazakhstan: No. RK-LS-5 No. 010367

Registration period: 03.08.2015 - 03.08.2020

KNF (drug is included in the Kazakhstan National Formulary of Medicines)

ED (Included in the List of drugs in the framework of the guaranteed volume of medical care, subject to purchase from a single distributor)

Limit purchase price in the Republic of Kazakhstan: 6 479.51 KZT

Instruction

Tradename

Prepenem ®

International non-proprietary name

Dosage form

Powder, for solution for intravenous administration

Compound

One vial contains

a sterile mixture of imipenem, cilastatin and sodium bicarbonate, including:

active substances: imipenema

(in terms of anhydrous imipenem) 500.0 mg

cilastatin sodium

(in terms of cilastatin) 500.0 mg,

excipient: sodium bicarbonate.

Description

Powder from white to slightly yellowish color.

Pharmacotherapeutic group

Antibacterial drugs for systemic use. Other beta-lactam antibacterials. Carbapenems. Imipenem and a dehydropeptidase inhibitor.

ATX code J01DH51

Pharmacological properties

Pharmacokinetics

After intravenous (IV) administration, the bioavailability of imipenem is 98%. It is rapidly and widely distributed in most tissues and body fluids. Binding to plasma proteins - 20%. The half-life is 1 hour. It is metabolized in the kidneys by hydrolysis of the beta-lactam ring under the action of renal dehydropeptidase.

Following intravenous administration of an imipenem/cilastatin solution, the time to peak plasma concentration (TCmax) is 20 minutes for both components. At the same time, the maximum concentration (Cmax) for imipenem/cilastatin reaches values from 21 to 58 µg/ml for imipenem and from 31 to 49 µg/ml for cilastatin. After the introduction of imipenem / cilastatin, Cmax decreases to a value of 1 μg / ml and below within 4-6 hours.

The elimination half-life for each of the components is 1 hour. Plasma protein binding is 20% for imipenem and 40% for cilastatin. Approximately 70% of intravenous imipenem/cilastatin is excreted by the kidneys within 10 hours. Urinary antibiotic concentrations greater than 10 µg/mL may persist for up to 8 hours following intravenous administration of imipenem/cilastatin. About 70% of cilastatin is excreted by the kidneys within 10 hours after intravenous administration of the drug.

After intravenous administration, imipenem / cilastatin is determined in the following tissues and environments of the human body: in the vitreous body of the eyeball, intraocular fluid, lung tissue, pleural fluid, peritoneal fluid, bile, cerebrospinal fluid, connective, bone tissues.

Pharmacodynamics

Prepenem ® - a broad-spectrum antibiotic consisting of two components: imipenem and cilastatin.

Imipenem inhibits bacterial cell wall synthesis and has a bactericidal effect against a wide range of Gram-positive and Gram-negative pathogens. Imipenem is active against those gram-positive species against which only narrow-spectrum beta-lactam antibiotics were previously active.

Cilastatin sodium, a competitive, reversible, and specific inhibitor of dihydropeptidase-I, is a renal enzyme that is metabolized and inactivated by imipenem, which deprives it of its own antibacterial activity, but does not affect the antibacterial activity of imipenem.

Action spectrum imipenem/cilastatin includes Pseudomonas aeruginosa, Staphylococcus aureus, Enterococcus faecalis, and Bacteroides fragilis, a diverse group of problematic pathogens that are generally resistant to other antibiotics.

Imipenem is resistant to destruction by bacterial beta-lactamase, which makes it effective against many microorganisms, such as Pseudomonas aeruginosa, Serratia spp. and Enterobacter spp., which are resistant to most beta-lactam antibiotics.

Antimicrobial spectrum imipenem/cilastatin includes virtually all clinically relevant pathogens.

Imipenem/cilastatin active iin vitro against aerobic gram-negative bacteria: Achromobacter spp., Acinetobacter spp. (formerly Mima - Herellea), Aeromonas hydrophila, Alcaligenes spp., Bordetella bronchicanis, Bordetella bronchiseptica, Bordetella pertussis, Brucella melitensis, Campylobacter spp., Capnocytophaga spp., Citrobacter spp. (including Citrobacter diversus, Citrobacter freundii), Eikenella corrodens, Enterobacter spp. (including Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter cloacae), Escherichia coli, Gardnerella vaginalis, Haemophilus influenzae, Haemophilus ducreyi (including beta-lactamase producing strains), Haemophilus parainfluenzae, Hafnia alvei, Klebsiella spp. (including Klebsiella oxytoca, Klebsiella pneumoniae, Klebsiella ozaenae), Legionella spp., Moraxella spp., Morganella morganii (formerly Proteus morganii), Neisseria gonorrhoeae (including strains that produce penicillinase), Neisseria meningitidis, Pasteurella multocida, Proteus spp . (including Proteus mirabilis, Proteus vulgaris) Plesiomonas shigelloides, Providencia spp. (including Providencia rettgeri (formerly Proteus rettgeri), Providencia stuartii), Pseudomonas spp. (including Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas pseudomallei, Pseudomonas putida, P.stutzeri), Salmonella spp. (including Salmonella typhi), Serratia spp. (including Serratia liquefaciens, Serratia marcescens), Shigella spp., Yersinia spp. (including Yersinia enterocolitica, Yersinia pseudotuberculosis);

Aerobic gram-positive bacteria: Bacillus spp., Enterococcus faecalis, Erysipelothrix rhusiopathiae, Listeria monocytogenes, Staphylococcus epidermidis (including penicillinase-producing strains), Staphylococcus saprophyticus, Streptococcus spp. group B (including Streptococcus agalactiae), Streptococcus spp. groups C, G, Streptococcus pneumoniae, Streptococcus viridans (including hemolytic alpha and gamma strains);

Anaerobic Gram-negative bacteria: Porph romonas asaccharolytica (formerly Bacteroides asaccharolytica), Prevotella bivia (formerly Bacteroides bivius), Prevotella disiens (formerly Bacteroides disiens), Prevotella intermedia (formerly Bacteroides intermedius), Bacteroides melaninogenicus, Bacteroides uniformis, Bilophila wadswerthia, Fusobacterium spp. (including Fusobacterium necrophorum, Fusobacterium nucleatum), Veillonella spp.;

Anaerobic gram-positive bacteria: Actinomyces spp., Clostridium spp. (including Clostridium perfringens), Eubacterium spp., Microaerophilic streptococcus, Peptococcus spp., Peptostreptococcus spp., Propionibacterium spp. (including Propionibacterium acnes), Bifidobacterium spp., Lactobacillus spp., Mobiluncus spp., Mycobacterium fortuitum, Mycobacterium smegmatis.

Xanthomonas maltophilia (formerly Pseudomonas maltophilia) and some strains of Pseudomonas cepacia are resistant to imipenem/cilastatin.

In vitro tests show that imipenem/cilastatin acts synergistically with aminoglycoside antibiotics against certain isolates of Pseudomonas aeruginosa.

Indications for use

Adults and children over 1 year of age to treat the following infections:

Complicated intra-abdominal infections

Severe pneumonia, including nosocomial pneumonia and ventilator-associated pneumonia

Birth and postpartum infections

Complicated urinary tract infections

Complicated skin and soft tissue infections

Prepenem ® may be used in the treatment of febrile neutropenic patients with suspected bacterial infection, in the treatment of patients with bacteremia occurring in combination with or suspected of having any of the above infections.

Official guidance on the proper use of antibacterial agents should be followed.

Dosage and administration

the daily dose depends on the type and severity of the infection, the isolated pathogen(s), kidney function and body weight of the patient.

Adults and teenagers

For patients with normal renal function (creatinine clearance > 70 ml/min/1.73m2), the following doses are recommended:

500mg/500mg every 6 hours OR

1000mg/1000mg every 8 hours OR every 6 hours.

It is recommended for suspected or proven infection associated with a less susceptible species of bacteria (eg, Pseudomonas aeruginosa) and for very severe infections (in febrile patients with neutropenia) to prescribe 1000 mg / 1000 mg every 6 hours.

Dose reduction is necessary when:

Creatinine clearance ≤70 ml/min/1.73m2 (see Table 1) or

body weight<70 кг.

Dose for Patients<70 кг будет рассчитываться по следующей формуле:

Body weight of the patient (kg) * standard dose of the drug

The maximum total daily dose should not exceed 4000 mg/4000 mg per day.

kidney failure

Dose determination for adult patients with impaired renal function:

1. Daily dose (ie 2000/2000, 3000/3000 or 4000/4000 mg) can generally be used in patients with normal renal function.

2. According to Table 1, it is advisable to reduce the dose of the drug in accordance with the patient's creatinine clearance. Duration of infusions - see subsection "Method of application".

Table 1: Dose Reduction in Adult Patients with Renal Impairment and Body Weight >70 kg*

* For patients with body weight<70 кг следует рассчитать дальнейшее пропорциональное снижение дозы путем деления массы тела больного (в кг) на 70 кг и умножения на соответствующую рекомендуемую дозу согласно табл.1.

** When using doses of 500mg/500mg in patients with creatinine clearance from 6 to 20ml/min/1.73m2, there is a risk of developing seizures.

Patients with creatinine clearance<5мл/мин/1.73м2

Prepenem ® should not be given to such patients unless they have received hemodialysis within 48 hours.

Patients on hemodialysis

When treating patients with creatinine clearance ≤5ml/min/1.73m2 on hemodialysis, it is recommended to use the doses shown in Table 1 for patients with creatinine clearance between 6 and 20 ml/min/1.73m2 (see Table 1).

Imipenem and cilastatin are cleared from the circulation during hemodialysis. The patient should receive Prepenem ® with an interval of 12 hours after the end of the hemodialysis session. Patients receiving hemodialysis, especially those with concomitant diseases of the central nervous system, should be carefully monitored. For patients on hemodialysis, Prepenem ® it is recommended only if the benefit outweighs the potential risk of developing seizures (see section "Special Instructions").

There are currently no reliable data to recommend the use of Prepenem. ® patients on peritoneal dialysis.

Liver failure

For patients with impaired liver function, dose adjustment is not required (see section "Pharmacodynamics / pharmacokinetics").

Application in geriatrics

For elderly patients without pathology from the side of the kidneys, dose changes are not required (see the section "Pharmacodynamics / pharmacokinetics").

Application in pediatrics

It is recommended that if infection is suspected or non-susceptible bacterial species (eg, Pseudomonas aeruginosa) and very severe infections (eg, febrile neutropenic patients) are identified, doses of 25/25 mg/kg every 6 hours are recommended.

For kids<1 года

Child population with renal insufficiency

Mode of application

Preparation of a solution for intravenous infusion

Add 100 ml of solvent to the powder vial. As a solvent, you can use: isotonic sodium chloride solution; 5% aqueous dextrose solution; 10% aqueous dextrose solution; a solution of 5% dextrose and 0.9% sodium chloride; a solution of 5% dextrose and 0.45% sodium chloride; a solution of 5% dextrose and 0.225% sodium chloride; a solution of 5% dextrose and 0.15% potassium chloride; mannitol 5% and 10%. The resulting solution (imipenem concentration 5 mg/ml) must be shaken until a clear liquid is formed. Differences in the color of the solution from yellow to colorless do not affect the activity of the drug.

To prepare a solution of Prepenem ® do not use solvents containing a salt of lactic acid (lactate).

Each dose ≤500 mg/500 mg should be administered intravenously over 20-30 minutes. Each dose > 500 mg/500 mg should be given over 40 to 60 minutes. If the patient develops nausea during the infusion, the rate of infusion may be reduced.

Side effects

In clinical studies (1723 patients received imipenem /

cilastatin intravenously), the most frequently reported systemic adverse reactions associated with this therapy were: nausea (2.0%), diarrhea (1.8%), vomiting (1.5%), rash (0.9%), fever (0.5%), arterial hypotension (0.4%), convulsions (0.4%), dizziness (0.3%), pruritus (0.3%), urticaria (0.2%), drowsiness ( 0.2%). Of the local adverse reactions, the most frequently identified were: phlebitis/thrombophlebitis (3.1%), pain at the injection site (0.7%), erythema at the injection site (0.4%) and hardening of the veins (0.2%). Also been reported: an increase in serum transaminases and alkaline phosphatase.

The following adverse reactions have been reported in clinical and post-marketing studies:

All adverse reactions are listed according to organ classification and frequency: very often (≥1/10), often (≥1/100 to<1/10), нечасто (≥1/1000 до <1/100), редко (≥ 1/10000 до <1/1000), очень редко (<1/10000) и неизвестная частота (может не быть оценена по имеющимся данным).

Within each frequency group, adverse effects are presented in descending order of severity.

System	Frequency	Side effects
Infections and manifestations		pseudomembranous colitis, candidiasis
Infections and manifestations	rarely	gastroenteritis
Diseases of the blood and lymphatic system		eosinophilia
		pancytopenia, neutropenia, leukopenia, thrombocytopenia, thrombocytosis
		agranulocytosis
	rarely	hemolytic anemia, bone marrow suppression
Diseases of the immune system		anaphylactic reactions
mental illness		mental disorders, including hallucinations and disorientation
Disorders of the nervous system		convulsions, myoclonic activity, dizziness, drowsiness
		encephalopathy, paresthesia, focal tremor, taste perversion
	rarely	exacerbation of myasthenia gravis, headache
ENT disorders		hearing loss
ENT disorders	rarely	tinnitus, dizziness
Heart disease	rarely	cyanosis, tachycardia, palpitations
Vascular diseases		thrombophlebitis
		hypotension
	rarely
Respiratory system disorders	rarely	shortness of breath, hyperventilation, sore throat
Gastrointestinal Disorders		diarrhea, nausea, vomiting. Drug-induced nausea and vomiting is more common in patients with granulocytopenia than in patients without it during treatment with imipenem/cilastatin
		staining of the tongue and/or teeth
	rarely	hemorrhagic colitis, abdominal pain, heartburn, glossitis, hypertrophy of tongue papillae, hypersalivation
Liver disease		liver failure, hepatitis
Liver disease	rarely	fulminant hepatitis
Diseases of the skin and subcutaneous tissue		rash, including exanthematous)
		hives, itching
		toxic epidermal necrolysis, angioedema, Stevens-Johnson syndrome, erythema multiforme, exfoliative dermatitis
	rarely	hyperhidrosis, skin changes
Diseases of the musculoskeletal system	rarely	polyarthralgia, pain in the thoracic spine
Diseases of the urinary system		acute renal failure, oliguria / anuria, polyuria, urine discoloration (harmless, not to be confused with hematuria). It is difficult to assess the role of imipenem/cilastatin in changes in renal function unless there are predisposing factors such as prerenal azotemia and renal insufficiency.
Diseases of the mammary glands and reproductive system	rarely	vulvar itching
General diseases and side effects in the area of drug administration		fever, local pain and induration, erythema at the injection site
	rarely	chest discomfort, asthenia/weakness
Research		increased transaminases and alkaline phosphatase in the blood serum
Research		positive direct Coombs reaction, prolongation of prothrombin time, decrease in hemoglobin, increase in bilirubin, increase in serum creatinine and urea

In pediatric practice

Children (≥3 months)

In a study that included 178 sick children ≥3 months of age, adverse reactions were consistent with data in adult patients.

Contraindications

Hypersensitivity to the active substances or to any of the excipients

Hypersensitivity to any other carbapenem antibacterial drug

Marked hypersensitivity (eg, anaphylactic reaction, severe skin reactions) to any other type of beta-lactam antibacterial agent (eg, penicillins or cephalosporins)

Children's age up to 1 year

Children with impaired renal function (serum creatinine >2 mg/l)

Adult patients with creatinine clearance less than 5 ml/min

Drug Interactions

Generalized seizures have been reported in patients treated with ganciclovir and imipenem/cilastatin. These drugs should not be given concomitantly unless the potential benefit outweighs the risk of complications.

The introduction of imipenem / cilastatin is accompanied by a decrease in the serum concentration of valproic acid with an associated risk of increased seizure activity (cases registered in clinical practice), therefore, during treatment with Prepenem ® monitoring of serum concentrations of valproic acid is recommended.

Prepenem ® should not be mixed in the same syringe with other antibiotics, while simultaneous, but isolated administration with other antibiotics (aminoglycosides) is allowed.

Simultaneous administration of antibiotics with warfarin may increase the anticoagulant effect of the latter. There are numerous reports of an increase in the anticoagulant effect of oral anticoagulants, including warfarin, in patients receiving antibiotics at the same time. The risks may vary depending on the type of infection, age and general condition of the patient, so the contribution of an antibiotic to an increase in INR (international normalized ratio) is difficult to assess. It is recommended to control INR, especially often during and immediately after the co-administration of antibiotics with oral anticoagulants.

Co-administration of imipenem/cilastatin and probenecid results in a minimal increase in plasma levels of imipenem and an increase in its plasma half-life. Urinary recovery of active (unmetabolized) imipenem is reduced by approximately 60% when imipenem/cilastatin is administered with probenecid. Co-administration of imipenem/cilastatin and probenecid doubled the plasma levels of cilastatin and its half-life, but had no effect on urinary recovery.

special instructions

When choosing imipenem/cilastatin for treatment in a particular patient, consideration should be given to prescribing carbapenem based on factors such as the severity of the infection, resistance to other antibiotics, and the risk of selecting carbapenem-resistant bacteria.

Hypersensitivity

Serious and sometimes fatal cases of hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam therapy. These reactions are more likely in people with a history of sensitivity to multiple allergens. Before starting treatment with Prepenem ® it is necessary to carefully question the patient regarding previous hypersensitivity reactions to carbapenems, penicillins, cephalosporins and other beta-lactams and allergens (see section "Contraindications").

Treatment should be discontinued immediately if an allergic reaction to Prepenem occurs. ® . Serious anaphylactic reactions require urgent emergency care.

From the side of the liver

Liver function should be carefully monitored during treatment with Prepenem. ® due to the risk of developing liver toxicity (for example, an increase in transaminases, the development of liver failure and fulminant hepatitis).

When appointing Prepenem ® in patients with liver disease, it is necessary to monitor liver function during treatment. Adjust doses of Prepenem ® optional (see "How to Use" section).

Hematology

During treatment with Prepenem ® a positive Coombs test (direct or indirect) may develop.

Antibacterial spectrum

Antibacterial spectrum of Prepenem should be taken into account before starting empiric treatment. ® , especially in conditions that threaten the life of the patient. In addition, care must be taken when prescribing Prepenem. ® due to the limited susceptibility of specific pathogens causing, for example, bacterial infection of the skin and soft tissues. Prepenem ® should not be given for the treatment of such infections until the pathogen has been identified, positive susceptibility has been determined and the pathogen is likely to respond to treatment. Co-administration of an appropriate anti-MRSA agent may be considered if MRSA infection is suspected or there is evidence indicated in the indications for use. Simultaneous use of Prepenem ® and an aminoglycoside may be indicated when a Pseudomonas aeruginosa infection is suspected or there is evidence of an indication approved in this leaflet (see section "Indications for use").

Interaction with valproic acid

Simultaneous use of Prepenem ® and valproic acid/sodium valproate is not recommended (see Drug Interactions section).

Clostridium difficile

When appointing Prepenem ® As with almost all antibiotics, antibiotic-associated and pseudomembranous colitis have been reported, ranging in severity from mild to life-threatening. It is important to keep this diagnosis in mind in patients who develop diarrhea during or after the use of Prepenem. ® (see section "Side effects"). For this category of patients, it is necessary to consider the possibility of discontinuing therapy with Prepenem. ® and prescribing a specific treatment for Clostridium difficile. It is not recommended to prescribe drugs that inhibit intestinal motility.

kidney failure

Prepenem ® may accumulate in patients with reduced renal function and cause adverse reactions from the central nervous system if the dose of the antibiotic is not adequately selected (see section "Method of application")

central nervous system

Such adverse reactions from the side of the central nervous system as myoclonic activity, convulsions, disorientation, confusion, which occurred when the recommended doses were exceeded, calculated on the basis of creatinine clearance and body weight of the patient, were identified. These adverse reactions were more frequently recorded in patients with CNS disorders (eg, brain damage or a history of seizures in the patient's history) and/or impaired renal function, in which accumulation of administered doses of the drug may occur. In this regard, it is recommended to strictly adhere to the calculations of the doses of the drug in these categories of patients (see the section "Method of administration and doses"). It is necessary to continue anticonvulsant therapy in patients who have already had a convulsive syndrome.

Particular vigilance should be observed in children with neurological symptoms and a history of seizures, especially in the presence of known risk factors for seizures or concomitant treatment with drugs that lower the seizure threshold.

If a fine tremor, clonic convulsions or seizures occur, an urgent consultation with a neurologist is necessary to prescribe anticonvulsant therapy. If CNS symptoms persist, the dose of Prepenem ® should be reduced or completely stopped taking the drug.

Patients with creatinine clearance ≤5 ml/min/1.73m2 should not receive Prepenem ® , unless hemodialysis was performed within 48 hours. For patients on hemodialysis, imipenem/cilastatin is only recommended if the benefit outweighs the potential risk of seizures (see Dosage and Administration section).

Pediatric population

Prepenem ® 500 mg / 500 mg contains 37.5 mg sodium (1.6 mmol), which should be taken into account when calculating the sodium content when choosing a diet.

Pregnancy and lactation

Pregnancy

There are no reliable controlled studies on the use of imipenem/cilastatin in pregnant women.

Studies in pregnant monkeys have shown reproductive toxicity. The potential risk to humans is unknown.

Prepenem ® should be used during pregnancy only if the benefit to the mother justifies the potential risk to the fetus.

Breast-feeding

Imipenem/cilastatin is found in human breast milk in small amounts. If the use of Prepenem ® recognized as necessary, it is necessary to compare the ratio of the benefits of feeding and the possible risk to the child

fertility

No data available regarding potential exposure to imipenem/

cilastatinan fertility functions of men or women.

Features of the effect of the drug on the ability to drive a vehicle or potentially dangerous mechanisms

Clinical studies to study the effect of the drug on the ability to drive vehicles have not been conducted. However, given the possibility of side effects (development of hallucinations and drowsiness) during treatment with Prepenem ® , special care must be taken when driving and operating potentially dangerous machinery.

Overdose

Symptoms: increased side effects of the drug, which may include: convulsions, confusion, tremor, nausea, vomiting, hypotension, bradycardia.

Treatment: There is no specific information on the treatment of overdose with imipenem/cilastitin. The drug is removed during hemodialysis, but the effectiveness of this procedure in case of an overdose of the drug is unknown.

Release form and packaging

500 mg of active substances are placed in vials hermetically sealed with rubber stoppers, crimped with aluminum caps or combined caps "FLIPP OFF".

Each bottle is labeled with a label made of label or writing paper, or a self-adhesive label imported. Each bottle, together with the approved instructions for medical use in the state and Russian languages, is placed in a cardboard box.

It is allowed to apply the text from the approved instructions for medical use in the state and Russian languages to the pack.