Imipenem-Belpharm 500 mg

Medicine trade name: Imipenim-Belpharm
Active ingredient (INN): Imipenem + cilastatin
Medicine form: powder for preparation of injection solution 250 mg/250 mg and 500 mg/500 mg
Description: white to pale-yellow tinted powder
Composition for 1 bottle:
Active substance:
Imipenem monohydrate (in terms of imipenem) – 250 mg or 500 mg.
Cilastatin sodium (in terms of cilastatin) – 250 mg or 500 mg.
Pharmaceutic group: antibiotic of carbapenem group.
ATX Code: J01DH51

Pharmacological properties
Beta-lactam antibiotic of wide spectrum of action. 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. Cilastatin does not have its own antibacterial activity and does not inhibit bacterial β-lactamase.
The drug is active against Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus faecalis and Bacteroides fragilis. Resistant to destruction by bacterial β-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. Antibacterial spectrum includes almost all clinically significant pathogenic microorganisms.
Is active against gram-negative aerobic bacteria: Achromobacter spp., Acinetobacter spp. (previously Mima-Herellea), Aeromonas hydrophila, Alcaligenes spp., Bordetella bronchicanis, Bordetella bronchiseptica, Bordetella pertussis, Brucella melitensis, Campylobacter spp., Capnocytophaga spp., Citrobacter spp. (Citrobacter diversus, Citrobacter freundii), Eikenella corrodens, Enterobacter spp. (Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter cloacae), Escherichia coli, Gardnerella vaginalis, Haemophilus ducreyi, Haemophilus influenzae including strains, which forms beta-lactamase), Haemophilus parainfluenzae, Hafnia alvei, Klebsiella spp. (Klebsiella oxytoca, Klebsiella ozaenae, Klebsiella pneumoniae), Moraxella spp., Morganella morganii (ранее Proteus morganii), Neisseria gonorrhoeae (including strains, which forms penicillinase), Neisseria meningitidis, Yersinia spp. (previously Pasteurella), Yersinia multocida, Yersinia enterocolitica, Yersinia pseudotuberculosis; Plesiomonas shigelloides, Proteus spp. (Proteus mirabilis, Proteus vulgaris), Providencia spp. (Providencia alcalifaciens, Providencia rettgeri (previously Proteus rettgeri), Providencia stuartii), Pseudomonas spp. (Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas pseudomallei, Pseudomonas putida, Pseudomonas stutzeri), Salmonella spp. (Salmonella typhi), Serratia spp. (Serratia marcescens, Serratia proteamaculans), Shigella spp; gram-positive anaerobic bacteria: Bacillus spp., Enterococcus faecalis, Erysipelothrix rhusiopathiae, Listeria monocytogenes, Nocardia spp., Pediococcus spp., Staphylococcus aureus (including strains, which forms penicillinase), Staphylococcus epidermidis (including strains, which forms penicillinase), Staphylococcus saprophyticus, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus group С, Streptococcus group G, green streptococci (including alpha- and gamma-hemolytic strains); gram-negative anaerobic bacteria: Bacteroides spp. (Bacteroides distasonis, Bacteroides fragilis, Prevotella melaninogenica (previously Bacteroides melaninogenicus), Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus), Bilophila wadsworthia, Fusobacterium spp. (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. (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. (stable to methicillin), Streptococcus spp. (group D), Stenotrophomonas maltophilia, Enterococcus faecium and some Pseudomonas cepacian strains are unstable to imipenem. Effective against many infections, caused by bacteria, stable to cephalosporins, aminoglycoside, penicillin. In vitro acts synergity with aminoglycoside against some Pseudomonas aeruginosa strains.

Pharmacokinetics
Cmax of imipenem while administrating in dose 500 mg during 20 minutes – mkg/ml. C_max of cilastatin when administrating in 500 mg during 20 minutes is – 31-49 mkg/ml. Connection with protein of imipenem plasma – 20%, of cilastatin – 40%. Distributed fast and well in most of tissues and fluids of organism. Highest concentrations reach in pleural effusion, peritoneal and interstitial fluids and reproductive organs. In lowest concentrations discovered in spinal fluid. 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 of channel secretion of imipenem cilastatin results in inhibiting its renal metabolism and accumulation in the urine in unchangeable way. Cilastatin is metabolized to N- acetyl connection. With intravenous administration, the half-life (T1/2) of imipenem and cilastatin in adults is 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 mainly by the kidneys (70-76% within 10 hours) by glomerular filtration (2/3) and active tubular secretion (1/3); 1-2% is excreted through the gastrointestinal tract and 20-25% through the extrarenal route (the mechanism is 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).

Indications for use
Infectious-inflammatory diseases, caused by sensitive microorganisms (polymicrobial or mixed aerobic-anaerobic infections):
- Lower respiratory tract infections;
- Urinatory tract infections;
- Intraabdominal infections;
- Skin and soft tissue infections;
- Bone and joint infections;
- Peritonitis;
- Sepsis;
- Endocarditis;
- Inflammatory diseases of pelvis organs.
Prevention of postoperative complications.

Method of preparing
Imipenem + cilastatin for infusion can not be mixed or added to other antibiotics.
For preparing the infusion solution is used following solvents: 0,9% sodium chloride solution, 5-10% aqueous dextrose solution, 5-10% Mannitol solution. In the ratio of 100 ml of solvent and 500 mg of imipenem. The concentration of imipenem in the resulting solution is 5 mg/ml.
Contents of the bottle are pre-dissolved in 10-20 ml of a suitable solvent.
Resulting solution can not be used for administration!
Solution is shaken well, after which placed in bottles or containers with the left part of solvent (80-90 ml). Overall volume of the solvent is 100 ml. For full transfer of the drug: 20 ml of previously resulted solution is added to the bottle, shaken well and transferred again to the bottle or container now with resulted solution. Only after this solution is ready for use.

Directions for use and dosage
Intravenous drip. Doses given below are calculated for body weight 70 kg or more and 70 ml/min/1.73 m² or more.
For patients with CC less than 70 ml/min/1.73 m² and/or lower body weight, the dose should be proportionally reduced.
Average therapeutic dose for adults (calculated based on imipenem) for intravenous administration is 1-2 g/day, divided into 3-4 administrations; the maximum daily dose is 4 g or 50 mg/kg, whichever is lower.
Patients with mild severity of infection - 250 mg 4 times a day, moderate severity - 500 mg 3 times / day or 1 g 2 times / day, severe - 500 mg 4 times / day, for an infection that threatens the patient’s life - 1 g 3-4 times / day.
A dose of imipenem less than or equal to 500 mg should be administered intravenously over 20-30 minutes. A 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 drug administration.
For the prevention of postoperative infections - 1 g during induction of anesthesia and 1 g after 3 hours. In the case of surgery with a high risk of infection (surgery on the colon and rectum), an additional 500 mg is administered 8 and 16 hours after general anesthesia.
Maximum daily doses for intravenous administration in patients with renal failure, depending on the severity of the infection and values (ml/min/1.73 m2) and body weight ≥70kg:
- for mild infection and 41-70 ml/min - 250 mg every 8 hours, CC 21-40 ml/min - 250 mg every 12 hours, 6-20 ml/min - 250 mg every 12 hours ;
- for moderate infection and 41-70 ml/min – 250 mg every 6 hours, CC 21-40 ml/min – 250 mg every 8 hours, 6-20 ml/min – 250 mg every 12 hours ;
- in severe cases (moderately sensitive strains, including Pseudomonas aeruginosa) and CC 41-70 ml/min – 500 mg every 6 hours, CC 21-40 ml/min – 500 mg every 8 hours, CC 6 -20 ml/min – 500 mg every 12 hours;
- in case of severe life-threatening infection and CC 41-70 ml/min – 750 mg every 8 hours, CC 21-40 ml/min – 500 mg every 6 hours, CC 6-20 ml/min – 500 mg after 12 hours
Patients with CC less than 5 ml/min are prescribed only if hemodialysis is performed no later than 48 hours after the drug infusion. Administration of the drug to such patients is recommended only in cases where the benefits of its use outweigh the potential risk of developing seizures. When treating patients with CC (creatinine clearance) less than 5 ml/min who are on hemodialysis, doses for patients with CC 6-20 ml/min and body weight less than 70 kg should be used (see below). The drug is administered after a hemodialysis session and then at 12-hour intervals from the moment the procedure is completed, and patients must be closely monitored (especially if they have diseases of the central nervous system).
Currently, there is insufficient data on the dosage regimen for preoperative prophylaxis in patients with CC less than 70 ml/min/1.73 m2.
The following is a dosage regimen for patients with impaired renal function and/or with a body weight of less than 70 kg.
a) Maximum daily dose 1 g.

b) Maximum daily dose 1,5 g

c) Maximum daily dose 2 g.

d) Maximum daily dose 3 g.

e) Maximum daily dose 4 g.

Currently there are no enough data for that to recommend patients the use of the drug, who are in peritoneal dialysis.
Children with body weight of 40 kg and more are prescribed the same dose as adults.
Children over 3 months and with body weight less than 40 kg – 15 mg/kg 4 times/day; maximum daily dose – 2g.
Use in elderly patients: it is should be kept in mind, that in elderly patients it is possible to be age disorder of renal function, which can demand the reduction of dose.
It is advisable to monitor renal excretory function.

Contraindications
- Pregnancy;
- Lactation period;
- Early childhood (to 3 months)
- In children with impaired renal function (concentration of serum creatinine is more than 2 mg/ml);
- Increased sensitivity to components of the drug, to carbapenem and other beta-lactam antibiotics.
With caution:
- CNS, GIT diseases (medical history), old age.

Side effects
From the 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 blood and lymphatic system: eosinophilia, leukopenia, neutropenia, agranulocytosis, thrombocytopenia, thrombocytosis, monocytosis, lymphocytosis, basophilia, decreased hemoglobin, prolongation of prothrombin time.
Laboratory indicators: 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: thrombophlebitis.
Other: candidiasis, taste disturbance.

Drug interactions
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).

Special instructions
Not recommended for treatment of meningitis.
Colors urine reddish.
Dosage form for intravenous administration should not be used for intramuscular 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 brain injuries or a history of seizures should continue throughout the period of treatment with the drug (to avoid side effects from the central nervous system).
Should be kept in mind, that in elderly patients it is possible to be age disorder of renal function, which requires the reduction of dose.
Use of drug during pregnancy and lactation period:
There were no studies with use of Imipenem-Belpharm for intravenous administration in pregnant women therefore drug should be used during pregnancy only in case, if benefits of its use justifies the potential risk for fetus.
Imipenem is discovered in breast milk of person. If use of Imipenem – Belpharm is considered necessary, then feeding of a child with a breast milk should be stopped.
Children with body weight of 40 kg and more:
Prescribed the same dose as to adults.
Children over 3 months and with body weight less than 40 kg:
15mg/kg 4 times/day; maximum daily dose – 2g.
Use in elderly patients:
Should be kept in mind that, in elderly patients it is possible to be age disorder of renal function, which requires the reduction of dose. It is advisable to monitor renal excretory function.
Store drug in a place out reach of children and do not use after expiration date.

Overdose
Symptoms: increased severity of side effects
Treatment: symptomatic. Imipenem and cilastatin are eliminated from the organism by hemodialysis. However effectivity of this procedure in overdose of the drug is unknown.

Release form
500 mg or 1000 mg vial for injection volume of 10 ml or 20 ml.
By 1 or 5 vials together with instructions of use in a cardboard box.
Packaging for hospitals: 36 vials with corresponding amount of instructions of use in group boxes.

Storage conditions
Store in dry place, protected from light at the temperature not higher than 25C
Store in a place out of reach of children.

Expiration date
Expiration date is 2 years
Do not use after expiration date, shown at the packaging.

Conditions for release from pharmacies
On prescription

Manufacturer/ name and address od organization, accepting claims (offers) regarding the quality of medicinal product in the territory of Republic of Uzbekistan
FE LLC “BELPHARM”, Republic of Uzbekistan, Tashkent city, Kichik Khalka yuli and Badamzar str., 37
www.belpharm.uz