Imicinem-TF (Powder) Instructions for Use

Marketing Authorization Holder

Triplepharm JV LLC (Republic of Belarus)

ATC Code

J01DH51 (Imipenem and cilastatin)

Active Substances

Imipenem (Rec.INN registered by WHO)

Cilastatin (Rec.INN registered by WHO)

Dosage Form

Imicinem-TF

Powder for solution for infusion 500 mg+500 mg: fl. 1 or 5 pcs.

Dosage Form, Packaging, and Composition

Powder for preparation of solution for infusion from white to light yellow color.

Excipients: sodium bicarbonate – 20 mg.

1 g – colorless glass vials with a volume of 10 ml (1) – cardboard packs.
1 g – colorless glass vials with a volume of 10 ml (5) – cardboard packs.
1 g – colorless glass vials with a volume of 10 ml (36) – cardboard packs (for hospitals).

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.

It 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.

It is 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

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

Plasma protein binding of imipenem is 20%, cilastatin is 40%. C_max of imipenem with intravenous administration of a dose of 250, 500 or 1000 mg over 20 minutes is 14-24, 21-58 and 41-83 µg/ml respectively; with intramuscular administration of 500 or 750 mg – 10 and 12 µg/ml respectively. C_max of cilastatin with intravenous administration of a dose of 250, 500 or 1000 mg over 20 minutes is 15-25, 31-49 and 56-80 µg/ml; with intramuscular administration of 500 or 750 mg – 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 effusion, peritoneal and interstitial fluids and reproductive organs. It is found in low concentrations in the 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 urine unchanged. Cilastatin is metabolized to an N-acetyl compound.

With intramuscular administration, T_1/2 of imipenem is 2-3 hours. With intravenous administration, T_1/2 of imipenem and cilastatin in adults is 1 hour, in children 2-12 years old – 1-1.2 hours, in newborns T_1/2 of imipenem is 1.7-2.4 hours, cilastatin – 3.8-8.4 hours; in case of impaired renal function T_1/2 of imipenem is 2.9-4 hours, cilastatin – 13.3-17.1 hours.

It is 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 bile with feces 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 received dose is removed).

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.

ICD codes

Dosage Regimen

Determine the dosage regimen individually based on the indication, severity of infection, patient’s renal function, body weight, and susceptibility of the causative organism.

Administer via intravenous infusion over 20-30 minutes or via intramuscular injection. Do not administer intravenously as a bolus.

For adults with normal renal function, the typical intravenous dosage is 250 mg to 1 g every 6 to 8 hours. Do not exceed a total daily dose of 4 g, or 50 mg/kg, whichever is lower.

For intramuscular administration in adults, use a dose of 500 mg or 750 mg every 12 hours. Do not exceed 1.5 g per day via the intramuscular route.

For pediatric patients (3 months and older, and weighing less than 40 kg), administer 15-25 mg/kg every 6 hours. Do not exceed 2-4 g per day.

Adjust the dosage in patients with renal impairment based on creatinine clearance (CrCl). For CrCl 30-70 mL/min, administer the standard dose every 8-12 hours. For CrCl 20-30 mL/min, administer the standard dose every 12 hours. For CrCl 5-20 mL/min, administer half the standard dose every 12 hours. For patients on hemodialysis, administer the dose post-dialysis as it is significantly removed.

For geriatric patients, consider age-related decline in renal function and adjust dosage accordingly.

Use the intramuscular formulation only for deep intramuscular injection; prepare the suspension for injection strictly according to the provided instructions using the specified solvents.

Adverse Reactions

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 (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, prolongation of prothrombin time, positive Coombs test.

From 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, multiform exudative erythema (including Stevens-Johnson syndrome), angioedema, toxic epidermal necrolysis (rarely), exfoliative dermatitis (rarely), fever, anaphylactic reactions.

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

Other candidiasis, taste disturbance.

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 suspension for intramuscular injection prepared using lidocaine hydrochloride as a solvent: hypersensitivity to local anesthetics of amide structure (shock, impaired intracardiac conduction).

With caution

CNS diseases, history of seizures, high seizure activity, anticonvulsant therapy with valproic acid (reduced therapy effectiveness), 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).

Use in Pregnancy and Lactation

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

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

Use in Renal Impairment

With caution: chronic renal failure (creatinine clearance less than 70 ml/min), patients on hemodialysis.

Pediatric Use

Contraindication – early childhood (up to 3 months). Contraindication: severe renal failure in children (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 function impairments, which may require a dose reduction.

Special Precautions

Not recommended for the treatment of meningitis.

Stains urine reddish.

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

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

In persons with a history of gastrointestinal diseases (especially colitis), there is an increased risk of developing pseudomembranous enterocolitis.

Antiepileptic drug therapy in patients with brain injuries or a history of seizures should continue throughout the treatment period (to avoid side effects from the central nervous system).

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

Effect on ability to drive vehicles and mechanisms

Given 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.

Drug Interactions

Pharmaceutically incompatible with lactic acid salt, 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 T_1/2 of imipenem (if high concentrations of imipenem are required, it is not recommended to use these drugs simultaneously).

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

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.