Imipenem+Cilastatin, 500 mg+500 mg powder

Pharmacotherapeutic group: Antibiotic, carbapenem

Pharmacological action

Beta-lactam antibiotic of broad spectrum. Inhibits the synthesis of the bacterial cell wall and has a bactericidal effect against a wide range of Gram-positive and Gram-negative microorganisms, aerobic and anaerobic.

Imipenem is a derivative of thienamycin and belongs to the group of carbapenems.

Cilastatin sodium inhibits dehydropeptidase, the enzyme that metabolizes imipenem in the kidneys, which significantly increases the concentration of unchanged imipenem in the urinary tract. Cilastin has no intrinsic antibacterial activity and does not inhibit the beta-lactamase of bacteria.

It is active against Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus faecalis and Bacteroides fragilis.

Resistant to degradation by bacterial beta-lactamase, making it effective against many microorganisms such as Pseudomonas aeruginosa, Serratia spp. and Enterobacter spp. which are resistant to most beta-lactam antibiotics.

The antibacterial spectrum includes virtually all clinically relevant pathogens.

Active against Gram-negative aerobic 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. Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter cloacae), Escherichia coli, Gardnerella vaginalis, Haemophilus ducreyi, Haemophilus influenzae (including beta-lactamase producing strains), Haemophilus parainfluenzae, Hafnia alvei, Klebsiella spp. (including Klebsiella oxytoca, Klebsiella ozaenae, Klebsiella pneumoniae), Moraxella spp, Morganella morganii (formerly Proteus morganii), Neisseria gonorrhoeae (including penicillinase-producing strains), Neisseria meningitidis, Yersinia spp.Yersinia multocida, Yersinia enterocolitica, Yersinia pseudotuberculosis; Plesiomonas shigelloides, Proteus spp. (including Proteus mirabilis, Proteus vulgaris), Providencia spp. Providencia alcalifaciens, 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 marcescens, Serratia proteamaculans), Shigella spp, Enterococcus faecalis, Erysipelothrix rhusiopathiae, Listeria monocytogenes, Nocardia spp., Pediococcus spp, Staphylococcus aureus (including penicillinase-producing strains), Staphylococcus epidermidis (including penicillinase-producing strains), Staphylococcus saprophyticus, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus group C, Streptococcus group G, green streptococci including alpha- and gamma-hemolytic strains); Gram-negative anaerobic bacteria: Bacteroides spp. (including Bacteroides distasonis, Bacteroides fragilis, Prevotella melaninogenica (formerly Bacteroides melaninogenicus), Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus), Bilophila wadsworthia, Fusobacterium spp, including (Fusobacterium necrophorum, Fusobacterium nucleatum), Porphyromonas asaccharolytica (previously Bacteroides asaccharolyticus), Prevotella bivia (previously Bacteroides bivius), Prevotella disiens (previously Bacteroides disiens), Prevotella intermedia (previously Bacteroides intermedius), Veillonella spp.; gram positive anaerobic bacteria: Actinomyces spp, Bifidobacterium spp., Clostridium spp. (including Clostridium perfringens), Eubacter spp., Lactobacillus spp, Microaerophilic streptococcus, Mobiluncus spp, Peptococcus spp, Peptostreptococcus spp, Propionibacterium spp. (including Propionibacterium acne); other microorganisms: Mycobacterium fortuitum, Mycobacterium smegmatis.Some Staphylococcus spp. (resistant to methicillin), Streptococcus spp. (group D), Stenotrophomonas maltophilia, Enterococcus faecium and some strains of Pseudomonas cepacia are not sensitive to imipenem.

It is effective against many infections caused by bacteria resistant to cephalosporins, aminoglycosides, penicillins. In vitro it acts synergistically with aminoglycosides against some strains of Pseudomonas aeruginosa.

Pharmacokinetics

The bioavailability of imipenem is 95% and that of cilastatin 75% when administered by injection.

The binding to plasma proteins of imipenem is 20%, that of cilastatin – 40%. C_max of imipenem when administered v/v in a dose of 250, 500 or 1000 mg for 20 min is 14-24, 21-58 and 41-83 µg/mL, respectively; when administered v/m in 500 or 750 mg is 10 and 12 µg/mL, respectively. C_max of cilastatin when administered v/v in a dose of 250, 500 or 1000 mg for 20 min is 15-25, 31-49 and 56-80 µg/mL; when administered v/v in 500 or 750 mg is 24 and 33 µg/mL, respectively.

It is rapidly and well distributed in most tissues and body fluids. The highest concentrations are achieved in pleural effusions, peritoneal and interstitial fluids, and reproductive organs. In low concentrations, it is found in CSF. V_d in adults is 0.23-0.31 l/kg, in children 2-12 years old – 0.7 l/kg, in newborns – 0.4-0.5 l/kg.

Blocking of tubular secretion of imipenem by cilastatin leads to inhibition of its renal metabolism and accumulation in the urine in unchanged form. Cilastatin is metabolized to N-acetyl compound.

When administered in m/m, the T_1/2 of imipenem is 2-3 h. When administered intravenously, T_1/2 of imipenem and cilastatin is 1 h in adults, 1-1.2 h in children 2-12 years old, in newborns T_1/2 of imipenem is 1.7-2.4 h, cilastatin 3.8-8.4 h; in impaired renal function T_1/2 imipenem 2.9-4 h, cilastatin 13.3-17.1 h.

Extracted primarily by the kidneys (70-76% within 10 h) by glomerular filtration (2/3) and active tubular secretion (1/3); 1-2% is eliminated through bile with feces and 20-25% by the extrarenal route (mechanism unknown).

Fast and efficient (73-90%) excretion by hemodialysis (a 3-hour session of intermittent hemofiltration removes 75% of the dose received).

Indications

Intra-abdominal infections; lower respiratory tract infections; genitourinary system infections; bone and joint infections; skin and soft tissue infections; pelvic organ infections; sepsis; bacterial endocarditis; prevention of postoperative infections; mixed infections; nosocomial infections.

Pharmacological effect

Pharmacotherapeutic group: Antibiotic, carbapenem

Pharmacological action

Broad-spectrum beta-lactam antibiotic. Suppresses the synthesis of bacterial cell walls and has a bactericidal effect against a wide range of gram-positive and gram-negative microorganisms, aerobic and anaerobic.

Imipenem is a derivative of thienamycin and belongs to the group of carbapenems.

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

Active against Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus faecalis and Bacteroides fragilis.

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.

The antibacterial spectrum includes almost all clinically significant pathogenic microorganisms.

Active against gram-negative aerobic 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 ducreyi, Haemophilus influenzae (including strains that produce beta-lactamase), Haemophilus parainfluenzae, Hafnia alvei, Klebsiella spp. (including Klebsiella oxytoca, Klebsiella ozaenae, Klebsiella pneumoniae), Moraxella spp., Morganella morganii (formerly Proteus morganii), Neisseria gonorrhoeae (including penicillinase-producing strains), Neisseria meningitidis, Yersinia spp. (formerly Pasteurella), incl. Yersinia multocida, Yersinia enterocolitica, Yersinia pseudotuberculosis; Plesiomonas shigelloides, Proteus spp. (including Proteus mirabilis, Proteus vulgaris), Providencia spp. (including Providencia alcalifaciens, 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 marcescens, Serratia proteamaculans), Shigella spp.; gram-positive aerobic bacteria: Bacillus spp., Enterococcus faecalis, Erysipelothrix rhusiopathiae, Listeria monocytogenes, Nocardia spp., Pediococcus spp., Staphylococcus aureus (including penicillinase-forming strains), Staphylococcus epidermidis (including penicillinase-forming strains), Staphylococcus saprophyticus, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus group C, Streptococcus group G, viridans streptococci including alpha and gamma hemolytic strains); gram-negative anaerobic bacteria: Bacteroides spp. (including Bacteroides distasonis, Bacteroides fragilis, Prevotella melaninogenica (formerly Bacteroides melaninogenicus), Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus), Bilophila wadsworthia, Fusobacterium spp., incl. (Fusobacterium necrophorum, Fusobacterium nucleatum), Porphyromonas asaccharolytica (formerly Bacteroides asaccharolyticus), Prevotella bivia (formerly Bacteroides bivius), Prevotella disiens (formerly Bacteroides disiens), Prevotella intermedia (formerly Bacteroides intermedius), Veillonella spp.; gram-positive anaerobic bacteria: Actinomyces spp., Bifidobacterium spp., Clostridium spp. (including Clostridium perfringens), Eubacter spp., Lactobacillus spp., Microaerophilic streptococcus, Mobiluncus spp., Peptococcus spp., Peptostreptococcus spp., Propionibacterium spp. (including Propionibacterium acne); others. microorganisms: Mycobacterium fortuitum, Mycobacterium smegmatis. Some Staphylococcus spp. (methicillin-resistant), Streptococcus spp. (group D), Stenotrophomonas maltophilia, Enterococcus faecium and some strains of Pseudomonas cepacia are not susceptible to imipenem.

Effective against many infections caused by bacteria resistant to cephalosporins, aminoglycosides, and penicillins. In vitro, it acts synergistically with aminoglycosides against some strains of Pseudomonas aeruginosa.

Pharmacokinetics

With intramuscular administration, the bioavailability of imipenem is 95%, cilastatin is 75%.

Plasma protein binding of imipenem is 20%, cilastatin is 40%. Cmax of imipenem when administered intravenously at a dose of 250, 500 or 1000 mg over 20 minutes – 14-24, 21-58 and 41-83 mcg/ml, respectively; with intramuscular administration of 500 or 750 mg – 10 and 12 μg/ml, respectively. Cmax of cilastatin when administered intravenously at a dose of 250, 500 or 1000 mg over 20 minutes – 15-25, 31-49 and 56-80 mcg/ml; with intramuscular administration of 500 or 750 mg – 24 and 33 mcg/ml, respectively.

Quickly and well distributed in most tissues and body fluids. The highest concentrations are achieved in pleural effusion, peritoneal and interstitial fluids and reproductive organs. Found in low concentrations in the CSF. Vd in adults – 0.23-0.31 l/kg, in children 2-12 years old – 0.7 l/kg, in newborns – 0.4-0.5 l/kg.

Blocking the tubular secretion of imipenem with cilastatin leads to inhibition of its renal metabolism and accumulation in the urine unchanged. Cilastatin is metabolized to the N-acetyl compound.

With intramuscular administration, T1/2 of imipenem – 2-3 hours. With intravenous administration, T1/2 of imipenem and cilastatin in adults – 1 hour, in children 2-12 years old – 1-1.2 hours, in newborns T1/2 of imipenem – 1.7-2.4 hours, cilastatin – 3.8-8.4 hours; in case of impaired renal function T1/2 of imipenem – 2.9-4 hours, cilastatin – 13.3-17.1 hours.

Excreted primarily by the kidneys (70-76% within 10 hours) by glomerular filtration (2/3) and active tubular secretion (1/3); 1-2% is excreted through bile with feces and 20-25% by extrarenal route (mechanism unknown).

Quickly and effectively (73-90%) is eliminated by hemodialysis (as a result of a 3-hour session of intermittent hemofiltration, 75% of the received dose is removed).

Special instructions

Not recommended for the treatment of meningitis.

Colors urine reddish.

The dosage form for intramuscular administration should not be used for intravenous administration and vice versa.

Before initiating therapy, a thorough medical history should be obtained regarding previous allergic reactions to beta-lactam antibiotics.

Individuals with a history of gastrointestinal diseases (especially colitis) have an increased risk of developing pseudomembranous enterocolitis.

Therapy with antiepileptic drugs in patients with a history of traumatic brain injury or seizures should be continued throughout the treatment period (to avoid side effects from the central nervous system).

It should be kept in mind that elderly patients are likely to have age-related renal impairment, which may require dose reduction.

Impact on the ability to drive vehicles and machinery

Considering the likelihood of developing side effects from the central nervous system, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Active ingredient

Imipenem, [Cilastatin]

Composition

Powder – 1 fl.:

Active substances:

imipenem (in the form of monohydrate) 500 mg, cilastatin (in the form of cilastatin sodium) 500 mg;

Excipients:

sodium bicarbonate 20 mg.

Pregnancy

Used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

The drug passes through breast milk in small quantities, so the issue of stopping breastfeeding during treatment should be decided.

Contraindications

Hypersensitivity (including to carbapenems and other beta-lactam antibiotics); pregnancy (only for “vital” indications); early childhood (up to 3 months); in children – severe renal failure (serum creatinine concentration more than 2 mg/dl).

For an intramuscular injection suspension prepared using lidocaine hydrochloride as a solvent: hypersensitivity to local anesthetics with amide structure (shock, intracardiac conduction disturbance).

With caution

Diseases of the central nervous system, history of seizures, high seizure activity, anticonvulsant therapy with valproic acid (reduced effectiveness of therapy), chronic renal failure (creatinine clearance less than 70 ml/min), patients on hemodialysis, elderly age, patients with a history of gastrointestinal diseases (including pseudomembranous colitis).

Side Effects

From the central nervous system and peripheral nervous system: myoclonus, mental disorders, hallucinations, confusion, epileptic seizures, paresthesia.

From the urinary system: oliguria, anuria, polyuria, acute renal failure (rare).

From the digestive system: nausea, vomiting, diarrhea, pseudomembranous enterocolitis, hepatitis (rare).

From the hematopoietic organs and hemostasis system: eosinophilia, leukopenia, neutropenia, agranulocytosis, thrombocytopenia, thrombocytosis, monocytosis, lymphocytosis, basophilia, decreased hemoglobin, prolonged prothrombin time, positive Coombs test.

From laboratory parameters: increased activity of liver transaminases and alkaline phosphatase, hyperbilirubinemia, hypercreatininemia, increased concentration of urea nitrogen; direct positive Coombs test.

Allergic reactions: skin rash, itching, urticaria, exudative erythema multiforme (including Stevens-Johnson syndrome), angioedema, toxic epidermal necrolysis (rare), exfoliative dermatitis (rare), fever, anaphylactic reactions.

Local reactions: skin hyperemia, painful infiltration at the injection site, thrombophlebitis.

Other: candidiasis, taste disturbance.

Interaction

Pharmaceutically incompatible with lactic acid salt and other antibacterial drugs.

When used simultaneously with penicillins and cephalosporins, cross-allergy is possible; exhibits antagonism towards other beta-lactam antibiotics (penicillins, cephalosporins and monobactams).

Ganciclovir increases the risk of developing generalized seizures.

Drugs that block tubular secretion slightly increase the plasma concentration and T1/2 of imipenem (if high concentrations of imipenem are required, the use of these drugs at the same time is not recommended).

Manufacturer

Kraspharma PJSC, Russia