Гримипенем®

General characteristics. Structure:

Active ingredients: 250 mg or 500 mg of an imipenem a monohydra (in an erescheta on impeny); 250 mg or 500 mg циластатин sodium (in recalculation in циластин).

Vspomagatelno substance: hydrocarbon sodium.

Beta лактамный an antibiotic of a broad spectrum of activity + the enzyme increasing concentration of an antibiotic.

Pharmacological properties:

Pharmacodynamics. Imipenem - beta лактамный an antibiotic of a broad spectrum of activity, is derivative a tiyenamitsina and treats group of karbapenem. Suppresses synthesis of a cell wall of bacteria and has bactericidal effect concerning a wide range of gram-positive and gram-negative aerobic and anaerobic microorganisms.

Tsilastatin of sodium inhibits dehydropeptidase - the enzyme metabolizing imipeny in kidneys that considerably increases concentration of not changed imipenem in urinary tract. Tsilastatin has no own antibacterial activity, does not oppress beta lactamelements of bacteria.

^{Гримипенем®} it is steady against destruction by bacterial beta lactamelements that does it effective concerning the majority of microorganisms producers beta лактамаз, such as Pseudomonas aeruginosa, Serratia spp. and Enterobacter spp., resistant to penicillin and cephalosporins.

^{Гримипенем®} it is active in the relation:
- gram-negative aerobic bacteria: Achromobacter spp., Acinetobacter spp., Aeromonas hydrophila, Alcaligenes spp., Bordetella bronchicanis, B. bronchiseptica, B. pertussis, Brucella melitensis, Campylobacter spp., Capnocytophaga spp., Citrobacter spp., C. diversus, C. freundii, Eikenella corrodens, Enterobacter spp., E. aerogenes, E. agglomerans, E. cloacae, Escherichia coli, Gardnerella vaginalis, Haemophilus ducreyi, H. influenzae (including the strains producing beta lactamelements), H. parainfluenzae, Hafnia alvei, Klebsiella spp. (K. oxytoca, K. ozaenae, K. pneumoniae), Moraxella spp., Morganella morganii, Neisseria gonorrhoeae (including the strains producing beta lactamelements), N. meningitidis, Pasteurella spp., Pasteurella multocida, Plesiomonas shigelloides, Proteus spp., P. mirabilis, P. vulgaris, Providencia spp., P. alcalifaciens, P. rettgeri, P. stuartii, Pseudomonas aeruginosa, P. fluorescens, P. pseudomallei, P. putida, P. stutzeri, Salmonella spp., including S. typhi, Serratia spp. (S. proteamaculans, S. marcescens), Shigella spp., Yersinia spp., Y.enterocolitica, Y. pseudotuberculosis;
- gram-positive aerobic bacteria: Bacillus spp., Enterococcus faecalis, Erysipelothrix rhusiopathiae, Listeria monocytogenes, Nocardia spp., Pediococcus spp., Staphylococcus aureus (including the strains producing penicillinases), S. epidermidis (including the strains producing penicillinases), S. saprophyticus, Streptococcus agalactiae, S. pneumoniae, S. pyogenes, the green streptococci, including alpha and gamma hemolitic strains, streptococci of groups C and G;
- gram-negative anaerobic bacteria: Bacteroides fragilis, Bacteroides spp. (including B. distasonis, B. ovatus, B. thetaiotaomicron, B. uniformis, B. vulgatus), Bilophila wadsworthia, Fusobacterium spp. (including F. necrophorum, F. nucleatum), Porphyromonas asaccharolytica, Prevotella bivia, P. disiens, P. intermedia, P. melaninogenica, Veillonella spp.;
- gram-positive anaerobic bacteria: Actinomyces spp., Bifidobacterium spp., Clostridium spp. (including S. perfringens), Eubacterium spp., Lactobacillus spp., Mobiluncus spp., mikroaerofilny streptococci, Peptococcus spp., Peptostreptococcus spp., Propionibacterium spp. (including P. acnes);
- other microorganisms: Mycobacterium fortuitum, Mycobacterium smegmatis.
In vitro works sinergidno with aminoglycosides for some strains of Pseudomonas aeruginosa.

Are insensitive to ^{Grimipenemu®}: Staphylococcus spp strains., steady against Methicillinum, Stenotrophomonas maltophilia, Enterococcus faecium and some strains of Burkholderia cepacia.

Pharmacokinetics. Upon termination of 20 minute infusion of 250+250, 500+500 or 1000+1000 mg of an imipenema/tsilastatin the maximum concentration of an imipenem in a blood plasma make 14-24, 21-58 and 41-83 mkg/ml; the maximum concentration of a tsilastatin - 15-25, 31-49 and 56-80 mkg/ml, respectively. 20% of the entered dose of an imipenem and 40% of a tsilastatin reversibly contact proteins of a blood plasma.

Imipenem is quickly distributed in many fabrics and liquids of an organism where the concentration exceeding minimum suppressing for sensitive microorganisms are created. The highest concentration are reached in a pleural exudate, peritoneal and intersticial liquids, reproductive organs. In low concentration it is found in cerebrospinal fluid. Distribution volume adults - 0,23-0,31 l/kg, at children have 2-12 years - 0,7 l/kg, newborns have 0,4 - 0,5 l/kg. Both components of drug are removed preferential by kidneys (70-76% during 10 h) by glomerular filtering (2/3) and active canalicular secretion (1/3); 1-2% are removed with bile and 20-25% - an extrarenal way (the mechanism is unknown). Blocking of canalicular secretion of an imipenem tsilastatiny leads to inhibition of his renal metabolism and accumulation in urine in not changed look. At in introduction an elimination half-life of an imipenem and a tsilastatin adults - about 1 hour, at newborns have 4,0-8,5 h, at elderly - 1,5 h. 

Imipenem and циластатин quickly and effectively (73-90%) are removed by means of a hemodialysis (during the 3-hour session of discontinuous haemo filtering 75% of the received dose are removed).

Indications to use:

- lower respiratory tract infections, the caused Staphylococcus aureus (a penicillinase - the producing strains), Streptococcus pneumoniae, Acinetobacter spp., Enterobacter spp., Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella spp., Pseudomonas aeruginosa, Serratia marcescens;

- infections of the urinary tract caused by Enterococcus faecalis, Staphylococcus aureus (a penicillinase - the producing strains), Enterobacter spp., Escherichia coli, Klebsiella spp., Morganella morganii, Proteus vulgaris, Providencia rettgeri, Pseudomonas aeruginosa;

- the intraabdominal infections caused by Enterococcus faecalis, Staphylococcus aureus (a penicillinase - the producing strains), Staphylococcus epidermidis, Citrobacter spp., Enterobacter spp., Escherichia coli, Klebsiella spp., Morganella morganii, Proteus spp., Pseudomonas aeruginosa, Bifidobacterium spp., Clostridium spp., Eubacterium spp., Peptococcus spp., Peptostreptococcus spp., Propionibacterium spp., Bacteroides spp., including B. fragilis, Fusobacterium spp;

- the infectious and inflammatory diseases of bodies of a small pelvis caused by Enterococcus faecalis, Staphylococcus aureus (a penicillinase - the producing strains), Staphylococcus epidermidis, Streptococcus agalactiae (Group B streptococci), Enterobacter spp., Escherichia coli, Gardnerella vaginalis, Klebsiella spp., Proteus spp., Bifidobacterium spp., Peptococcus spp., Peptostreptococcus spp., Propionibacterium spp., Bacteroides spp., including B. fragilis;

- the bacterial septicaemia caused by Enterococcus faecalis, Staphylococcus aureus (a penicillinase - the producing strains), Enterobacter spp., Escherichia coli, Klebsiella spp., Pseudomonas aeruginosa, Serratia spp., Bacteroides spp., including B. fragilis;

- the infections of bones and joints caused by Enterococcus faecalis, Staphylococcus aureus (a penicillinase - the producing strains), Staphylococcus epidermidis, Enterobacter spp., Pseudomonas aeruginosa;

- the infections of skin and soft tissues caused by Enterococcus faecalis, Staphylococcus aureus (a penicillinase - the producing strains), Staphylococcus epidermidis, Acinetobacter spp., Citrobacter spp., Enterobacter spp., Escherichia coli, Klebsiella spp., Morganella morganii, Proteus vulgaris, Providencia rettgeri, Pseudomonas aeruginosa, Serratia spp., Peptococcus spp., Peptostreptococcus spp., Bacteroides spp., including B. fragilis, Fusobacterium spp.;

- the bacterial endocarditis caused by Staphylococcus aureus (a penicillinase - the producing strains);

- polymicrobial and the multi-infections caused by aerobic-anaerobic microflora;

- prevention of postoperative infectious complications.

Route of administration and doses:

It is entered in/in kapelno. The dosage form for should not be entered into uses intramusculary.

Average therapeutic dose for adults with the body weight of bigger or equal 70 kg and normal function of kidneys (the clearance of creatinine (CC) of 70 ml/min. / 1.73 ^sq.m and more) - 1-2 g/days (counting on imipeny), divided into 3-4 introductions; the maximum daily dose - 4 g or 50 mg/kg, depending on what dose will be smaller.

Depending on weight of an infection, the following doses ^{of Grimipenema®} are recommended: at the easy course of an infection and neslozhnenny infections of urinary tract - on 250 mg (hereinafter - counting on imipeny) 4 times a day; a medium-weight current - 500 mg 3 times a day or 1 g 2 times a day; a heavy current - 500 mg 4 times a day; at an infection, life-threatening the patient, - 1 g 3-4 times a day.

For prevention of postoperative infections - 1 g ^{of Grimipenema®} during an introduction anesthesia. In case of surgical intervention with a high risk of development of an infection (operation on thick and a rectum) in addition enter on 500 mg in 8 and 16 h after the end of operation.

For patients with clearance of creatinine less than 70 ml/min. / 1.73 ^sq.m and/or with a body weight less than 70 kg it is necessary to reduce in proportion a dose (see below):

Easy course of an infection (mode of 250 mg each 6 h)
Body weight	Clearance of creatinine, ml/min. / 1.73 sq.m
	> 71	41-70	21-40	6-20
> 71	250 mg each 6 h	250 mg each 8 h	250 mg each 12 h	250 mg each 12 h
60	250 mg each 8 h	125 mg each 6 h	250 mg each 12 h	125 mg each 12 h
50	125 mg each 6 h	125 mg each 6 h	125 mg each 8 h	125 mg each 12 h
40	125 mg each 6 h	125 mg each 8 h	125 mg each 12 h	125 mg each 12 h
30	125 mg each 8 h	125 mg each 8 h	125 mg each 12 h	125 mg each 12 h

 

Medium-weight course of an infection (mode of 500 mg each 8 h)
Body weight	Clearance of creatinine, ml/min. / 1.73 sq.m
	> 71	41-70	21-40	6-20
> 71	500 mg each 8 h	250 mg each 6 h	250 mg each 8 h	250 mg each 12 h
60	250 mg each 6 h	250 mg each 8 h	250 mg each 8 h	250 mg each 12 h
50	250 mg each 6 h	250 mg each 8 h	250 mg each 12 h	250 mg each 12 h
40	250 mg each 8 h	125 mg each 6 h	125 mg each 8 h	125 mg each 12 h
30	125 mg each 6 h	125 mg each 8 h	125 mg each 8 h	125 mg each 12 h

 

Heavy course of an infection (mode of 500 mg each 6 h)
Body weight	Clearance of creatinine, ml/min. / 1.73 sq.m
	> 71	41-70	21-40	6-20
> 71	500 mg each 6 h	500 mg each 8 h	250 mg each 6 h	250 mg each 12 h
60	500 mg each 8 h	250 mg each 6 h	250 mg each 8 h	250 mg each 12 h
50	250 mg each 6 h	250 mg each 6 h	250 mg each 8 h	250 mg each 12 h
40	250 mg each 6 h	250 mg each 8 h	250 mg each 12 h	250 mg each 12 h
30	250 mg each 8 h	125 mg each 6 h	125 mg each 8 h	125 mg each 12 h

 

Heavy course of an infection (mode of 1000 mg each 8 h)
Body weight	Clearance of creatinine, ml/min. / 1.73 sq.m
	> 71	41-70	21-40	6-20
> 71	1000 each 8 h	500 mg each 6 h	500 mg each 8 h	500 mg each 12 h
60	750 mg each 8 h	500 mg each 8 h	500 mg each 8 h	500 mg each 12 h
50	500 mg each 6 h	500 mg each 8 h	250 mg each 6 h	250 mg each 12 h
40	500 mg each 8 h	250 mg each 6 h	250 mg each 8 h	250 mg each 12 h
30	250 mg each 6 h	250 mg each 8 h	250 mg each 8 h	250 mg each 12 h

 

Life-threatening infections (mode of 1000 mg each 6 h)
Body weight	Clearance of creatinine, ml/min. / 1.73 sq.m
	> 71	41-70	21-40	6-20
> 71	1000 mg each 6 h	750 mg each 8 h	500 mg everyone	6 h 500 mg each 12 h
60	1000 mg each 8 h	750 mg each 8 h	500 mg everyone	8 h 500 mg each 12 h
50	750 mg each 8 h	500 mg each 6 h	500 mg everyone	8 h 500 mg each 12 h
40	500 mg each 6 h	500 mg each 8 h	250 mg everyone	6 h 250 mg each 12 h
30	500 mg each 8 h	250 mg each 6 h	250 mg each 8 h	250 mg each 12 h

The patient with KK / 1.73 ^sq.m appoint less than 5 ml/min. only if each 48 h the hemodialysis is carried out. At the patients who are on a hemodialysis, ^Grimipenem® should be entered in the doses recommended for patients with clearance of creatinine of 6-20 ml/min. / 1,73 to sq.m right after the session of a hemodialysis and through 12-hour intervals from the moment of completion of the procedure.

At children, since 3-month age, with body weight to 40 kg, the single dose makes 15 mg/kg which is entered by each 6 hours. The maximum daily dose makes 2 g.

To children with the body weight of 40 kg and more appoint the same doses, as the adult (see the table above).

Rules of preparation of solution and introduction ^{of Grimipenem®} (imipeny 500 mg and циластатин 500 mg), bottles glass 125 ml: for preparation of infusion solution add 100 ml of solvent to the bottle containing 0,5 g of an imipenem. As solvent it is necessary to use the following infusional environments: 0.9% solution of sodium of chloride, 5% dextrose solution, the aqueous solution containing 5% of a dextrose and 0.9% of sodium of chloride, the aqueous solution containing 5% of a dextrose and 0.45% of sodium of chloride, the aqueous solution containing 5% of a dextrose and 0.225% of sodium of chloride, the aqueous solution containing 5% of a dextrose and 0.15% of potassium of chloride, 5% or 10% solution of Mannitolum, 10% dekstoroza solution. The received solution (concentration of an imipenem of 5 mg/ml) needs to be stirred up before formation of transparent liquid. Distinctions of an okrashennost of solution from yellow to colourless do not influence activity of drug.

^{Гримипенем®} (imipeny 500 mg and циластатин 500 mg), bottles glass 30 ml.

Preparation of infusion solution is carried out in two steps:
1) for primary dissolution with powder of an antibiotic add 10-20 ml of one of the following solvents to a bottle: 0.9% solution of sodium of chloride, 5% dextrose solution, the aqueous solution containing 5% of a dextrose and 0.9% of sodium of chloride, the aqueous solution containing 5% of a dextrose and 0.45% of sodium of chloride, the aqueous solution containing 5% of a dextrose and 0.225% of sodium of chloride, the aqueous solution containing 5% of a dextrose and 0.15% of potassium of chloride, 5% or 10% solution of Mannitolum, 10% dekstoroza solution; then the bottle is well stirred up;

2) the received suspension or solution by means of the sterile syringe are transferred to the bottle containing 80-90 ml of the compatible infusional environment used for primary dissolution. The total amount of solvent - 100 ml.

Completely to transfer drug to solution for infusions: add 10-20 ml of the received solution to a bottle; the bottle is well stirred up; then both solutions combine.

Enter intravenously kapelno. Duration of infusion depends on the chosen dose: 250-500 mg enter in 20-30 min.; 750 mg - 1000 mg - in 40-60 min.

Ready solution for infusions (concentration of an imipenem of 5 mg/ml and less) can be stored at the room temperature within 4 hours or during 24 h in the refrigerator at a temperature of 4 °C.

Features of use:

It is not recommended for treatment of meningitis. At patients with instructions on diseases of the central nervous system it is necessary to apply with care and to follow the recommended dosages, avoiding exceeding of the specified dose.

Paints urine in reddish color.

At the persons having in the anamnesis of a disease of digestive tract, especially large intestine the increased risk of development of pseudomembranous colitis is noted.

Therapy by antiepileptic medicines at patients with brain injuries or epileptic seizures in the anamnesis has to continue the entire period of treatment ^{of Grimipenemom®} in order to avoid side effects from the central nervous system.

At elderly patients existence of age renal failures is probable that can demand a dose decline.

Side effects:

From a nervous system: myoclonia, mental disturbances, hallucinations, confusion of consciousness, epileptic seizures, paresthesias.

From an urinary system: oliguria, anury, polyuria, acute renal failure (seldom).

From the alimentary system: nausea, vomiting, diarrhea, pseudomembranous colitis, hepatitis (seldom).  

From bodies of a hemopoiesis and system of a hemostasis: eosinophilia, leukopenia, neutropenia, agranulocytosis, thrombocytopenia, thrombocytosis, monocytosis, lymphocytosis, basophilia, decrease in hemoglobin, lengthening of a prothrombin time; false positive test of Koombs.
Changes of laboratory indicators: increase in activity of "hepatic" transaminases and alkaline phosphatase, hyperbilirubinemia, giperkreatininemiya, increase in concentration of an urea nitrogen.

Allergic reactions: skin rash, itch, small tortoiseshell, multiformny exudative erythema (including Stephens-Johnson's syndrome), Quincke's disease, toxic epidermal necrolysis (seldom), exfoliative dermatitis (seldom), fever, anaphylactic reactions.

Local reactions: a dermahemia, painful infiltrate in an injection site, thrombophlebitis.

Others: candidiasis, taste disturbance.

Interaction with other medicines:

Pharmaceutical it is incompatible with salts of lactic acid (lactate), solutions of other antibiotics.

At simultaneous use with penicillin and cephalosporins the cross allergy is possible; with others beta лактамными antibiotics (penicillin, cephalosporins and monobaktama) observe antagonism of action.

At simultaneous use with gantsikloviry the risk of development of generalized spasms increases.

The medicines blocking canalicular secretion slightly increase concentration in plasma and Т½ an imipinema (if high concentration of an imipenem are required, it is not recommended to apply these medicines at the same time).

Contraindications:

Hypersensitivity to one of drug components, and also other karbapenema, beta лактамным to antibiotics, penicillin and cephalosporins; pregnancy (only according to "vital" indications), early children's age (up to 3 months); children have a heavy renal failure (concentration of serumal creatinine more than 2 mg/dl).

With care appoint at diseases of the central nervous system, in the period of a lactation, to advanced age.

 

Storage conditions:

List B. In the dry, protected from light place, at a temperature not above 25 °C.

Issue conditions:

According to the recipe

Packaging:

(500 mg + 500 mg) drug in bottles glass with a capacity of 30 ml.

(500 mg + 500 mg) drug in bottles glass (bottles) with a capacity of 125 ml. 

1 bottle with a capacity of 30 ml with the application instruction or 1 bottle with a capacity of 125 ml complete with a connecting tube (or without it) is placed in a pack from a cardboard.