Imipenem + Cilastatin (Powder) Instructions for Use

ATC Code

J01DH51 (Imipenem and Cilastatin)

Active Substances

Imipenem (Rec.INN registered by WHO)

Cilastatin (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antibiotic of the carbapenem group

Pharmacotherapeutic Group

Antibiotic-carbapenem + dehydropeptidase inhibitor

Pharmacological Action

Broad-spectrum beta-lactam antibiotic. It suppresses 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 carbapenem group.

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-lactamase.

The drug is active against Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus faecalis and Bacteroides fragilis. It 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. 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 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. (formerly Pasteurella), including 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-producing strains), Staphylococcus epidermidis (including penicillinase-producing 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 including (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), Eubacterium 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. (methicillin-resistant), 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

C_max of imipenem after IV administration of a dose of 250, 500 or 1000 mg over 20 min is 14-24, 21-58 and 41-83 µg/ml, respectively. C_max of cilastatin after IV administration of a dose of 250, 500 or 1000 mg over 20 min is 15-25, 31-49 and 56-80 µg/ml. Plasma protein binding of imipenem is 20%, cilastatin is 40%. It 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. It is found in low concentrations 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.

Blocking of the tubular secretion of imipenem by cilastatin leads to inhibition of its renal metabolism and accumulation in the urine unchanged. Cilastatin is metabolized to an N-acetyl compound. After IV administration, T_1/2 of imipenem and cilastatin in adults is 1 h, in children 2-12 years old – 1-1.2 h, in newborns T_1/2 of imipenem is 1.7-2.4 h, cilastatin – 3.8-8.4 h; in case of impaired renal function T_1/2 of imipenem is 2.9-4 h, cilastatin – 13.3-17.1 h. It is excreted mainly by the kidneys (70-76% within 10 h) by glomerular filtration (2/3) and active tubular secretion (1/3); 1-2% is excreted through the gastrointestinal tract and 20-25% by extrarenal route (mechanism unknown).

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

Indications

Infectious and inflammatory diseases caused by susceptible microorganisms (polymicrobial or mixed aerobic-anaerobic infections)

• Lower respiratory tract infections;
• Urinary tract infections;
• Intra-abdominal infections;
• Skin and soft tissue infections;
• Bone and joint infections;
• Peritonitis;
• Sepsis;
• Endocarditis;
• Inflammatory diseases of the pelvic organs.

Prevention of postoperative complications.

ICD codes

Dosage Regimen

Powder

IV drip. The doses below are calculated for a body weight of 70 kg and more and a CrCl of 70 ml/min/1.73 sq.m and more. For patients with a CrCl of less than 70 ml/min/1.73 sq.m and/or lower body weight, the dose should be proportionally reduced.

The average therapeutic dose for adults (calculated as imipenem) when administered IV is 1-2 g/day, divided into 3-4 administrations; the maximum daily dose is 4 g or 50 mg/kg, whichever is lower.

For patients with mild severity of infection – 250 mg 4 times/day, moderate severity – 500 mg 3 times/day or 1 g 2 times/day, severe severity – 500 mg 4 times/day, for life-threatening infection, – 1 g 3-4 times/day.

An imipenem dose less than or equal to 500 mg should be administered IV over 20-30 min. A dose over 500 mg should be administered IV over 40-60 min. Patients who experience nausea during the infusion should have the infusion rate slowed.

For prevention of postoperative infections – 1 g during induction anesthesia and 1 g – after 3 h. 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 h after general anesthesia.

Maximum daily doses for IV administration in patients with renal failure depending on the severity of the infection and CrCl values (ml/min/1.73 sq.m) and body weight ≥70 kg

• For mild infection and CrCl 41-70 ml/min – 250 mg every 8 h, CrCl 21-40 ml/min – 250 mg every 12 h, CrCl 6-20 ml/min – 250 mg every 12 h;
• For moderate infection and CrCl 41-70 ml/min – 250 mg every 6 h, CrCl 21-40 ml/min – 250 mg every 8 h, CrCl 6-20 ml/min – 250 every 12 h;
• For severe course (moderately sensitive strains, including Pseudomonas aeruginosa) and CrCl 41-70 ml/min – 500 mg every 6 h, CrCl 21-40 ml/min – 500 mg every 8 h, CrCl 6-20 ml/min – 500 mg every 12 h;
• For severe life-threatening infection, and CrCl 41-70 ml/min – 750 mg every 8 h, CrCl 21-40 ml/min– 500 mg every 6 h, CrCl 6-20 ml/min – 500 mg every 12 h.

Patients with CrCl 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 those cases where the benefit of its use outweighs the potential risk of seizures. When treating patients with CrCl less than 5 ml/min, on hemodialysis, doses for patients with CrCl 6-20 ml/min and body weight less than 70 kg should be used (see below). The drug is administered after the hemodialysis session and then at 12-hour intervals from the end of the procedure, with careful monitoring of patients (especially if they have diseases of the central nervous system).

Currently, there is insufficient data on the dosing regimen for preoperative prophylaxis in patients with CrCl less than 70 ml/min/1.73 sq.m.

The dosing regimen for patients with impaired renal function and/or body weight less than 70 kg is given below.

a) Maximum daily dose 1 g

Currently, there is insufficient data to recommend the use of the drug in patients on peritoneal dialysis.

Children with a body weight of 40 kg and more are prescribed the same doses as adults. Children over 3 months of age and with a body weight of less than 40 kg – 15 mg/kg 4 times/day; maximum daily dose – 2 g.

Preparation of solution for IV infusion

Imipenem+Cilastatin for IV infusion should not be mixed or added to other antibiotics.

The following solvents are used to prepare the infusion solution: 0.9% sodium chloride solution, 5% aqueous dextrose solution, 10% aqueous dextrose solution, 5% dextrose and 0.9% sodium chloride solution. In a ratio of 100 ml of solvent per 500 mg of imipenem. The concentration of imipenem in the resulting solution is 5 mg/ml.

20 ml and 30 ml vials

When using the drug in 20 ml or 30 ml vials, the contents of the vial are first dissolved in 10 ml of a suitable solvent.

The resulting solution cannot be used for administration!

The solution is shaken well and then transferred to a vial or container with the remaining part of the solvent (90 ml). The total volume of solvent is 100 ml. For complete transfer of the drug: add 20 ml of the previously obtained solution to the vial, shake well and transfer again to the vial or container with the already obtained solution. Only after this is the solution ready for use.

Adverse Reactions

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 enterocolitis, hepatitis (rarely).

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

Laboratory parameters increased activity of hepatic transaminases and alkaline phosphatase, hyperbilirubinemia, hypercreatininemia, increased blood urea nitrogen concentration; direct positive Coombs test.

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

Local reactions thrombophlebitis.

Other candidiasis, taste disturbance.

Contraindications

• Pregnancy;
• Lactation period;
• Early childhood (up to 3 months);
• In children with impaired renal function (serum creatinine concentration more than 2 mg/dl);
• Hypersensitivity to the components of the drug, to carbapenems and other beta-lactam antibiotics.

With caution

CNS diseases, gastrointestinal tract diseases (including in anamnesis), elderly age.

Use in Pregnancy and Lactation

The drug is contraindicated for use during pregnancy and lactation.

Use in Renal Impairment

IV drip. The doses below are calculated for a body weight of 70 kg and more and a CrCl of 70 ml/min/1.73 sq.m and more. For patients with a CrCl of less than 70 ml/min/1.73 sq.m and/or lower body weight, the dose should be proportionally reduced.

The average therapeutic dose for adults (calculated as imipenem) when administered IV is 1-2 g/day, divided into 3-4 administrations; the maximum daily dose is 4 g or 50 mg/kg, whichever is lower.

For patients with mild severity of infection – 250 mg 4 times/day, moderate severity – 500 mg 3 times/day or 1 g 2 times/day, severe severity – 500 mg 4 times/day, for life-threatening infection, – 1 g 3-4 times/day.

An imipenem dose less than or equal to 500 mg should be administered IV over 20-30 min. A dose over 500 mg should be administered IV over 40-60 min. Patients who experience nausea during the infusion should have the infusion rate slowed.

For prevention of postoperative infections – 1 g during induction anesthesia and 1 g – after 3 h. 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 h after general anesthesia.

Maximum daily doses for IV administration in patients with renal failure depending on the severity of the infection and CrCl values (ml/min/1.73 sq.m) and body weight ≥70 kg

• For mild infection and CrCl 41-70 ml/min – 250 mg every 8 hours, CrCl 21-40 ml/min – 250 mg every 12 hours, CrCl 6-20 ml/min – 250 mg every 12 hours;
• For moderate infection and CrCl 41-70 ml/min – 250 mg every 6 hours, CrCl 21-40 ml/min – 250 mg every 8 hours, CrCl 6-20 ml/min – 250 mg every 12 hours;
• For severe infection (moderately susceptible strains, including Pseudomonas aeruginosa) and CrCl 41-70 ml/min – 500 mg every 6 hours, CrCl 21-40 ml/min – 500 mg every 8 hours, CrCl 6-20 ml/min – 500 mg every 12 hours;
• For severe, life-threatening infection and CrCl 41-70 ml/min – 750 mg every 8 hours, CrCl 21-40 ml/min – 500 mg every 6 hours, CrCl 6-20 ml/min – 500 mg every 12 hours.

Patients with CrCl less than 5 ml/min should be prescribed the drug only if hemodialysis is performed no later than 48 hours after the drug infusion.

Administration to such patients is recommended only in cases where the benefit of its use outweighs the potential risk of seizures.

When treating patients with CrCl less than 5 ml/min on hemodialysis, doses for patients with CrCl 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 end of the procedure, with careful monitoring of patients required (especially in the presence of central nervous system diseases).

Currently, there is insufficient data on the dosing regimen for preoperative prophylaxis in patients with CrCl less than 70 ml/min/1.73 sq.m.

The dosing regimen for patients with impaired renal function and/or body weight less than 70 kg is provided below.

a) Maximum daily dose 1 g

Currently, there is insufficient data to recommend the use of the drug in patients on peritoneal dialysis.

Children with body weight 40 kg and more are prescribed the same doses as adults. Children over 3 months and with body weight less than 40 kg – 15 mg/kg 4 times/day; maximum daily dose – 2 g.

Pediatric Use

Children with body weight 40 kg and more are prescribed the same doses as adults. Children over 3 months and with body weight less than 40 kg – 15 mg/kg 4 times/day; maximum daily dose – 2 g.

Contraindicated

• Early childhood (under 3 months);
• In children with impaired renal function (serum creatinine concentration more than 2 mg/dl).

Geriatric Use

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

Special Precautions

Not recommended for the treatment of meningitis.

Stains urine reddish in color.

The dosage form for IV administration should not be used for IM administration and vice versa.

Before starting therapy, a thorough history should be taken regarding previous allergic reactions to beta-lactam antibiotics.

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

Therapy with antiepileptic drugs in patients with head injuries or a history of seizures should be continued throughout the treatment period with the drug (to avoid side effects from the CNS).

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

Overdose

Symptoms: possible increase in side effects.

Treatment: symptomatic. Imipenem and Cilastatin are hemodialyzable. However, the effectiveness of this procedure in case of drug overdose is unknown.

Drug Interactions

Pharmaceutically incompatible with lactic acid salt, other antibacterial drugs.

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

Ganciclovir increases the risk of generalized seizures.

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

3 years.

Do not use after the expiration date. Storage conditions

Store in a dry place, protected from light, at a temperature not exceeding 25°C (77°F). Keep out of reach of children. Prescription status By prescription.

Dispensing Status

Rx Only

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.