Grimipenem^® (Powder) Instructions for Use

Marketing Authorization Holder

PFC Prebend, LLC (Russia)

ATC Code

J01DH51 (Imipenem and Cilastatin)

Active Substances

Imipenem (Rec.INN registered by WHO)

Cilastatin (Rec.INN registered by WHO)

Dosage Form

Grimipenem®

Powder for solution for infusion 500 mg+500 mg: vial 1 pc.

Dosage Form, Packaging, and Composition

Powder for solution for infusion white or almost white with a yellowish tint.

Excipients: sodium bicarbonate.

Glass vials with a capacity of 30 ml (1) – cardboard boxes.
Glass vials with a capacity of 125 ml (1) – cardboard boxes.
Glass vials with a capacity of 125 ml (1) complete with a connecting tube – cardboard boxes.

Clinical-Pharmacological Group

Antibiotic of the carbapenem group

Pharmacotherapeutic Group

Antibiotic-carbapenem + dehydropeptidase inhibitor

Pharmacological Action

Imipenem is a broad-spectrum beta-lactam antibiotic, a derivative of thienamycin, and belongs to the carbapenem group. It suppresses the synthesis of the bacterial cell wall and has a bactericidal effect against a wide range of gram-positive and gram-negative aerobic and anaerobic microorganisms.

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 has no intrinsic antibacterial activity and does not inhibit bacterial beta-lactamases.

Grimipenem^® is resistant to destruction by bacterial beta-lactamases, making it effective against most beta-lactamase-producing microorganisms, such as Pseudomonas aeruginosa, Serratia spp., and Enterobacter spp., which are resistant to penicillins and cephalosporins.

Grimipenem^® is active against gram-negative aerobic bacteria Achromobacter spp., Acinetobacter spp., 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 beta-lactamase-producing strains), Haemophilus parainfluenzae, Hafnia alvei, Klebsiella spp. (Klebsiella oxytoca, Klebsiella ozaenae, Klebsiella pneumoniae), Moraxella spp., Morganella morganii, Neisseria gonorrhoeae (including beta-lactamase-producing strains), Neisseria meningitidis, Pasteurella spp., Pasteurella multocida, Plesiomonas shigelloides, Proteus spp., Proteus mirabilis, Proteus vulgaris, Providencia spp., Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas pseudomallei, Pseudomonas putida, Pseudomonas stutzeri, Salmonella spp., including Salmonella typhi, Serratia spp. (Serratia proteamaculans, Serratia marcescens), Shigella spp., Yersinia spp., Yersinia enterocolitica, Yersinia pseudotuberculosis; gram-positive aerobic bacteria: Bacillus 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, viridans streptococci, including alpha- and gamma-hemolytic strains, streptococci of groups C and G; gram-negative anaerobic bacteria Bacteroides fragilis, Bacteroides spp. (including Bacteroides distasonis, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus), Bilophila wadsworthia, Fusobacterium spp. (including Fusobacterium necrophorum, Fusobacterium nucleatum), Porphyromonas asaccharolytica, Prevotella bivia, Prevotella disiens, Prevotella intermedia, Prevotella melaninogenica, Veillonella spp., gram-positive anaerobic bacteria: Actinomyces spp., Bifidobacterium spp., Clostridium spp. (including Clostridium perfringens), Eubacterium spp., Lactobacillus spp., Mobiluncus spp., microaerophilic streptococci, Peptococcus spp., Peptostreptococcus spp., Propionibacterium spp. (including Propionibacterium acnes); other microorganisms Mycobacterium fortuitum, Mycobacterium smegmatis.

In vitro, it acts synergistically with aminoglycosides against some strains of Pseudomonas aeruginosa.

Strains of Staphylococcus spp. resistant to methicillin, Stenotrophomonas maltophilia, Enterococcus faecium, and some strains of Burkholderia cepacia are not susceptible to Grimipenem^®.

Pharmacokinetics

After the end of a 20-minute infusion of 500+500 mg imipenem/cilastatin, the C_max of imipenem in blood serum is 21-58 µg/ml; C_max of cilastatin is 31-49 µg/ml, respectively. 20% of the administered dose of imipenem and 40% of cilastatin are reversibly bound to plasma proteins. Imipenem is rapidly and well distributed in most tissues and body fluids. The highest concentrations are achieved in pleural effusion, peritoneal and interstitial fluids, and reproductive organs. Low concentrations are found in the cerebrospinal fluid. 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. Both components of the drug are 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 intestines and 20-25% by non-renal routes (mechanism unknown). Blocking the tubular secretion of imipenem by cilastatin leads to inhibition of its renal metabolism and accumulation in the urine unchanged. With intravenous administration, T_1/2 of imipenem and cilastatin in adults is about 1 hour, in newborns – 4-8.5 hours, in the elderly – 1.5 hours.

Imipenem and Cilastatin are rapidly and effectively (73-90%) removed by hemodialysis (during a 3-hour session of intermittent hemofiltration, 75% of the received dose is removed).

Indications

• Infections of the lower respiratory tract caused by Staphylococcus aureus (penicillinase-producing strains), Acinetobacter spp., Enterobacter spp., Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella spp., Serratia marcescens;
• Infections of the urinary tract caused by Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Enterobacter spp., Escherichia coli, Klebsiella spp., Morganella morganii, Proteus vulgaris, Providencia rettgeri, Pseudomonas aeruginosa;
• Intra-abdominal infections caused by Enterococcus faecalis, Staphylococcus aureus (penicillinase-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.;
• Gynecological infections caused by Enterococcus faecalis, Staphylococcus aureus (penicillinase-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;
• Bacterial septicemia caused by Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Enterobacter spp., Escherichia coli, Klebsiella spp., Pseudomonas aeruginosa, Serratia spp., Bacteroides spp., including B. fragilis;
• Infections of bones and joints caused by Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Staphylococcus epidermidis, Enterobacter spp., Pseudomonas aeruginosa;
• Infections of the skin and soft tissues caused by Enterococcus faecalis, Staphylococcus aureus (penicillinase-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.;
• Bacterial endocarditis caused by Staphylococcus aureus (penicillinase-producing strains).

Prevention of postoperative infectious complications.

ICD codes

Dosage Regimen

Administered intravenously by drip. The dosage form for intravenous use should not be administered intramuscularly.

The average therapeutic dose for adults with a body weight greater than or equal to 70 kg and normal renal function (creatinine clearance (CrCl) 70 ml/min/1.73 m² and above) is 1-2 g/day (based on Imipenem), divided into 3-4 administrations; the maximum daily dose is 4 g or 50 mg/kg, whichever is lower.

Depending on the severity of the infection, the following doses of Grimipenem^® are recommended: for mild infections and uncomplicated urinary tract infections – 250 mg (here and below – based on Imipenem) 4 times/day; moderate infections – 500 mg 3 times/day or 1 g 2 times/day; severe infections – 500 mg 4 times/day; for life-threatening infections, – 1 g 3-4 times/day.

For prevention of postoperative infections – 1 g of Grimipenem^® during induction anesthesia. In the case of surgical intervention with a high risk of developing infection (surgery on the colon and rectum), an additional 500 mg is administered 8 and 16 hours after the end of the operation.

For patients with CrCl less than 70 ml/min/1.73 m² and/or body weight less than 70 kg, the dose should be proportionally reduced (see table below).

Table. 1. Dosing of Grimipenem^® in patients with body weight less than 70 kg and/or impaired renal function (dose calculation based on imipenem).

Patients with CrCl less than 5 ml/min/1.73 m² are prescribed only if hemodialysis is performed every 48 hours. In patients on hemodialysis, Grimipenem^® should be administered in doses recommended for patients with creatinine clearance of 6-20 ml/min/1.73 m², immediately after the hemodialysis session and at 12-hour intervals from the completion of the procedure.

For children, starting from 3 months of age, with a body weight up to 40 kg, a single dose is 15 mg/kg, administered every 6 hours. The maximum daily dose is 2 g.

Children with a body weight of 40 kg and more are prescribed the same doses as adults (Table 1.)

Rules for solution preparation and administration

To prepare the infusion solution, add 100 ml of solvent to the vial containing 0.5 g of imipenem. The following infusion media should be used as solvents: 0.9% sodium chloride solution, 5% dextrose solution, an aqueous solution containing 5% dextrose and 0.9% sodium chloride. The concentration of imipenem in the resulting solutions is 5 mg/ml. Administer intravenously by drip. The duration of infusion depends on the chosen dose: 250-500 mg is administered over 20-30 minutes; 750 – 1000 mg – over 40-60 minutes.

Adverse Reactions

Imipenem/cilastatin therapy is usually well tolerated; adverse reactions with the indicated dosages and administration regimens develop rarely and in most cases resolve on their own.

From the nervous system myoclonus, mental disorders, hallucinations, confusion, epileptic seizures, paresthesia.

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

From the digestive system nausea, vomiting, diarrhea, pseudomembranous colitis, hepatitis (rarely).

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

Changes in laboratory parameters increased activity of hepatic transaminases and alkaline phosphatase, hyperbilirubinemia, hypercreatininemia, increased blood urea nitrogen concentration.

Allergic reactions skin rash, itching, urticaria, multiform exudative erythema (including Stevens-Johnson syndrome), angioneurotic edema, toxic epidermal necrolysis (rarely), exfoliative dermatitis (rarely), fever, anaphylactic reactions.

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

Other candidiasis, taste disturbance.

Contraindications

• Pregnancy (only for vital indications);
• Early childhood (up to 3 months);
• In children – severe renal failure (serum creatinine concentration greater than 2 mg/dl);
• Hypersensitivity to one of the components of the drug, as well as to other carbapenems, beta-lactam antibiotics, penicillins and cephalosporins.

With caution

CNS diseases, lactation period, old age.

Use in Pregnancy and Lactation

Contraindicated in pregnancy (only for vital indications), use with caution during lactation.

Use in Renal Impairment

The average therapeutic dose for adults with a body weight greater than or equal to 70 kg and normal renal function (creatinine clearance (CrCl) 70 ml/min/1.73 m² and more) is 1-2 g/day (calculated as Imipenem), divided into 3-4 administrations; the maximum daily dose is 4 g or 50 mg/kg, whichever is the smaller dose.

Depending on the severity of the infection, the following doses of Grimipenem^® are recommended: for mild infections and uncomplicated urinary tract infections – 250 mg (here and further – calculated as Imipenem) 4 times/day; moderate infections – 500 mg 3 times/day or 1 g 2 times/day; severe infections – 500 mg 4 times/day; for life-threatening infections, – 1 g 3-4 times/day.

For prevention of postoperative infections – 1 g of Grimipenem^® during induction anesthesia. In the case of surgical intervention with a high risk of infection development (surgery on the colon and rectum), an additional 500 mg is administered 8 and 16 hours after the end of the operation.

For patients with CrCl less than 70 ml/min/1.73 m² and/or body weight less than 70 kg, the dose should be proportionally reduced (see table below).

Table. 1. Dosing of Grimipenem^® in patients with body weight less than 70 kg and/or impaired renal function (doses calculated as imipenem).

Patients with CrCl less than 5 ml/min/1.73 m² are prescribed only if hemodialysis is performed every 48 hours. In patients on hemodialysis, Grimipenem^® should be administered in doses recommended for patients with creatinine clearance of 6-20 ml/min/1.73 m², immediately after the hemodialysis session and at 12-hour intervals from the end of the procedure.

Pediatric Use

In children, starting from 3 months of age, with a body weight up to 40 kg, a single dose is 15 mg/kg, administered every 6 hours. The maximum daily dose is 2 g.

Children with a body weight of 40 kg and more are prescribed the same doses as adults.

Contraindicated

• Early childhood (up to 3 months);
• In children – severe renal failure (serum creatinine concentration greater than 2 mg/dl).

Geriatric Use

Elderly patients may have age-related renal impairment, which may require a dose reduction.

Special Precautions

Not recommended for the treatment of meningitis. In patients with a history of CNS diseases, it should be used with caution and the recommended dosages should be followed, avoiding exceeding the specified dose.

Stains urine a reddish color.

Persons with a history of gastrointestinal diseases, especially of the colon, have an increased risk of developing pseudomembranous colitis.

Therapy with antiepileptic drugs in patients with brain injuries or a history of epileptic seizures should continue throughout the entire period of treatment with Grimipenem^® to avoid CNS side effects.

Elderly patients may have age-related renal impairment, which may require a dose reduction.

Overdose

No data.

Drug Interactions

Pharmaceutically incompatible with lactic acid salts (lactate), solutions of other antibiotics.

When used concomitantly with penicillins and cephalosporins, cross-allergy is possible; with other beta-lactam antibiotics (penicillins, cephalosporins and monobactams), antagonism of action is observed.

When used concomitantly with ganciclovir, the risk of developing generalized seizures increases.

Drugs that block tubular secretion slightly increase the plasma concentration and T_1/2 of imipenem (if high concentrations of imipenem are required, the concomitant use of these drugs is not recommended).

Storage Conditions

List B. In a dry place, protected from light, at a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

Shelf life – 2 years. Do not use after the expiration date,

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.