Tiepenem^® (Powder) Instructions for Use

Marketing Authorization Holder

Elfa SPC, JSC (Russia)

Manufactured By

Ruzpharma, LLC (Russia)

ATC Code

J01DH51 (Imipenem and cilastatin)

Active Substances

Imipenem (Rec.INN registered by WHO)

Cilastatin (Rec.INN registered by WHO)

Dosage Form

Tiepenem®

Powder for solution for infusion 500 mg+500 mg: vial 1 or 10 pcs.

Dosage Form, Packaging, and Composition

Powder for solution for infusion from white to light yellow, fine-crystalline.

Excipients: sodium bicarbonate – 20 mg.

Colorless glass vials (1) – cardboard packs.
Colorless glass vials (10) – cardboard packs.
Colorless glass vials (10) – plastic trays.

Clinical-Pharmacological Group

Antibiotic of the carbapenem group

Pharmacotherapeutic Group

Antibiotic, carbapenem

Pharmacological Action

Tiepenem^® consists of two components.

1) Imipenem, the first representative of a new class of beta-lactam antibiotics – thienamycins.

2) Cilastatin – a specific enzyme inhibitor that inhibits the metabolism of imipenem in the kidneys and significantly increases the concentration of unchanged imipenem in the urinary tract. Cilastatin has no intrinsic antibacterial activity and does not inhibit bacterial beta-lactamase.

A broad-spectrum beta-lactam antibiotic.

The drug inhibits bacterial cell wall synthesis and has a bactericidal effect against a wide range of gram-positive and gram-negative microorganisms, aerobic and anaerobic.

Imipenem is a thienamycin derivative, belonging to the carbapenem group.

Cilastatin inhibits dehydropeptidase, an enzyme that metabolizes imipenem in the kidneys, which significantly increases the concentration of unchanged imipenem in the urinary tract.

Imipenem is resistant to destruction by bacterial beta-lactamase, making it effective against many microorganisms such as Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa, Serratia spp., Enterobacter spp., which are resistant to most beta-lactam antibiotics, as well as anaerobes (Bacteroides fragilis). The antibacterial spectrum includes almost all clinically significant pathogenic microorganisms.

Active against the following microorganisms in vitro, as well as in vivo: gram-negative aerobes (Acinetobacter spp., Citrobacter spp., Enterobacter spp., Escherichia coli, Gardnerella vaginalis, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella spp., Morganella morganii, Proteus vulgaris, Providencia rettgeri, Pseudomonas aeruginosa, Serratia spp., including Serratia marcescens); gram-positive aerobes (Enterococcus faecalis, Staphylococcus aureus (including penicillinase-producing strains), Staphylococcus epidermidis (including penicillinase-producing strains), Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes; gram-negative anaerobes (Bacteroides spp., including Bacteroides fragilis, Fusobacterium spp.); gram-positive anaerobes (Bifidobacterium spp., Clostridium spp., Eubacterium spp., Peptococcus spp., Peptostreptococcus spp., Propionibacterium spp.).

Imipenem has a bactericidal effect in vitro against the following microorganisms: gram-positive aerobes (Bacillus spp., Listeria monocytogenes, Nocardia spp., Staphylococcus saprophyticus, Streptococcus groups C, G and viridans group); gram-negative aerobes (Aeromonas hydrophila, Alcaligenes spp., Capnocytophaga spp., Haemophilus ducreyi, Neisseria gonorrhoeae, including penicillinase-producing strains, Pasteurella spp., Providencia stuartii); gram-negative anaerobes (Prevotella bivia, Prevotella disiens, Prevotella melaninogenica, Veillonella spp.).

Not susceptible Enterococcus faecium, methicillin-resistant Staphylococcus spp., Xanthomonas maltophilia, Pseudomonas cepacia.

Acts synergistically with aminoglycosides in vitro against some strains of Pseudomonas aeruginosa.

Pharmacokinetics

Distribution

The maximum concentration (C_max) of imipenem after IV administration at a dose of 250, 500, or 1000 mg is reached within 20 min – 14-24, 21-58, and 41-83 mcg/ml, respectively. C_max of cilastatin after IV administration at a dose of 250, 500, or 1000 mg is reached within 20 min – 15-25, 31-49, and 56-80 mcg/ml. Plasma protein binding of imipenem is 20%, cilastatin – 40%. 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. Found in low concentrations in cerebrospinal fluid (CSF). V_d in adults – 0.23-0.31 L/kg, in children aged 2-12 years – 0.7 L/kg, in newborns – 0.4-0.5 L/kg.

Metabolism and Excretion

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. After IV administration, the half-life (T_1/2) of imipenem and cilastatin in adults is 1 h, in children aged 2-12 years – 1-1.2 h, in newborns T_1/2 of imipenem is 1.7-2.4 h, cilastatin – 3.8-8.4 h; in renal impairment T_1/2 of imipenem is 2.9-4 h, cilastatin – 13.3-17.1 h.

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 non-renal routes (mechanism unknown). Imipenem and cilastatin are rapidly and effectively (73-90%) removed by hemodialysis (75% of the administered dose is removed during a 3-hour session of intermittent hemofiltration).

Indications

Infectious and inflammatory diseases caused by microorganisms sensitive to imipenem

• 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 Bacteroides fragilis, Fusobacterium spp.;
• Lower respiratory tract infections caused by Streptococcus pneumoniae, Staphylococcus aureus (penicillinase-producing strains), Acinetobacter spp., Enterobacter spp., Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella spp., Serratia marcescens;
• Urinary tract infections caused by Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Enterobacter spp., Escherichia coli, Klebsiella spp., Morganella morganii, Proteus vulgaris, Providencia rettgeri, Pseudomonas aeruginosa;
• Skin and soft tissue infections 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 Bacteroides fragilis, Fusobacterium spp.;
• Bone and joint infections caused by Streptococcus pyogenes, Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Staphylococcus epidermidis, Enterobacter spp., Pseudomonas aeruginosa;
• Bacterial septicemia caused by Streptococcus pneumoniae, Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Enterobacter spp., Escherichia coli, Klebsiella spp., Pseudomonas aeruginosa, Serratia spp., Bacteroides spp., including Bacteroides fragilis;
• Infective endocarditis caused by Staphylococcus aureus (penicillinase-producing strains);
• 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 Bacteroides fragilis.

Prevention of postoperative complications in at-risk patients with a high probability of developing postoperative infectious complications, as well as in patients with a high risk of intraoperative infection during surgery.

ICD codes

Dosage Regimen

Intravenously (IV) drip.

The drug dosing guidelines indicate the amount of imipenem to be administered. The calculation of the total daily dose should be based on the severity of the infection, renal function, and patient body weight. Administration is divided into several doses.

The doses below are calculated for adult patients with a body weight of 70 kg or more and a CrCl of 70 ml/min/1.73 m² or more. For adult patients with CrCl less than 70 ml/min/1.73 m² and/or lower body weight, the dose should be proportionally reduced.

The average therapeutic dose for adults (calculated by imipenem) for IV 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.

For adult patients with mild infections – 250 mg 4 times/day (total daily dose 1 g), moderate severity – 500 mg 3 times/day or 1 g 2 times/day (total daily dose 1.5-2 g), severe – 500 mg 4 times/day (total daily dose 2 g), for life-threatening infection – 1 g 3-4 times/day.

For prevention of postoperative infections in adults – 1 g during induction anesthesia and 1 g – after 3 h. In case of surgery with a high risk of infection (colorectal surgery) additionally administer 500 mg after 8 and 16 h after general anesthesia.

Maximum daily doses for IV administration in adult patients (body weight >70 kg) with renal impairment depending on the severity of infection and CrCl values (ml/min/1.73 m²)

• 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 mg every 12 h;
• For severe course (highly sensitive strains) and CrCl 41-70 ml/min – 500 mg every 8 h, CrCl 21-40 ml/min – 250 mg every 6 h, CrCl 6-20 ml/min – 250 mg 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.

For adult 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 (dose calculation by imipenem).

Maximum daily dose 1 g

For adult patients with CrCl less than 5 ml/min, the drug is administered only if hemodialysis will be performed no later than 48 hours later. When treating adult patients with CrCl less than 5 ml/min/1.73m² on hemodialysis, the dosing regimen recommendations for patients with CrCl 6-20 ml/min should be applied. Such patients, especially those with CNS diseases, should be closely monitored. The use of the drug in adult patients on hemodialysis is recommended only in cases where the benefit of treatment outweighs the potential risk of seizures. Imipenem and cilastatin are removed by hemodialysis, so the drug is administered after the procedure and then at 12-hour intervals.

Currently, there is insufficient data on the dosing regimen for preoperative prophylaxis in adult patients with CrCl less than 70 ml/min/1.73 m².

For children weighing 40 kg and more – the same doses as for adults. For children over 3 months and weighing less than 40 kg – 15 mg/kg 4 times/day; maximum daily dose – 2 g.

According to clinical studies, the efficacy and safety of imipenem+cilastatin for IV administration in elderly patients over 65 years do not differ from those in younger individuals. However, given the characteristic reduced functions of the cardiovascular system, liver, kidneys in this age group, as well as the presence of concomitant diseases and concomitant drug therapy, caution should be exercised in dose selection, adhering to the lower limits of recommended doses. Monitoring of renal excretory function is advisable. The condition of the kidneys in elderly patients cannot be fully determined solely by measuring blood urea nitrogen or creatinine. Determination of CrCl is recommended for dose selection in such patients.

Preparation of Solution

The following solvents are used for the preparation of the infusion solution: 0.9% sodium chloride solution, 5% dextrose solution, 10% dextrose solution, 5% dextrose and 0.9% sodium chloride solution at a ratio of 500 mg of imipenem per 100 ml of solvent.

When using the drug in 100 ml, 115 ml, or 125 ml vials, the contents are dissolved in 100 ml of solvent added to the vial. The resulting solution must be shaken until a clear liquid is formed. When using the drug in 20 ml or 30 ml vials, the vial contents are first dissolved in 10 ml of a suitable solvent. The resulting solution must not be used for administration!

After dilution, 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 the solvent is 100 ml. For complete transfer of the drug (drug residue on the vial walls), 20 ml of the previously obtained solution is added to the vial, shaken well, and transferred again to the vial or container with the already obtained solution. Only after this is the solution ready for use.

The concentration of imipenem in the resulting solution is 5 mg/ml. Each 250-500 mg is administered by intravenous drip infusion over 20-30 minutes, and each 750 mg-1 g is administered over 40-60 minutes. Patients who experience nausea during the infusion should have the infusion rate reduced.

Adverse Reactions

Nervous System Disorders encephalopathy, tremor, confusion, myoclonus, paresthesia, vertigo, headache, mental disorders including hallucinations, seizures.

Renal and Urinary Disorders oliguria, anuria, polyuria, proteinuria, erythrocyturia, leukocyturia, cylindruria, increased bilirubin concentration in urine and urine discoloration, increased plasma concentrations of blood urea nitrogen and creatinine, acute renal failure.

Gastrointestinal Disorders nausea, vomiting, diarrhea, pseudomembranous colitis, hemorrhagic colitis, hepatitis (including fulminant), hepatic failure, jaundice, gastroenteritis, abdominal pain, glossitis, tongue papillae hypertrophy, teeth or tongue staining, pharyngeal pain, hypersalivation, heartburn.

Blood and Lymphatic System Disorders pancytopenia, bone marrow depression, hemolytic anemia, eosinophilia, leukopenia, neutropenia, agranulocytosis, thrombocytopenia, thrombocytosis, monocytosis, lymphocytosis, leukocytosis, basophilia, decreased hemoglobin and hematocrit, prolonged prothrombin time.

Investigations increased activity of hepatic transaminases and alkaline phosphatase, hyperbilirubinemia, increased LDL concentration, false-positive direct Coombs test, hyponatremia, hyperkalemia, hypochloremia.

Immune System Disorders skin rash, itching, urticaria, erythema multiforme exudativum (including Stevens-Johnson syndrome), angioedema, toxic epidermal necrolysis, exfoliative dermatitis, fever, anaphylactic reactions.

Ear and Labyrinth Disorders hearing loss, tinnitus, taste disturbance.

Respiratory, Thoracic and Mediastinal Disorders chest discomfort, dyspnea, hyperventilation.

Cardiac Disorders palpitations, tachycardia.

General Disorders and Administration Site Conditions skin hyperemia, painful infiltration at the injection site, phlebitis/thrombophlebitis, infection at the injection site, vein induration.

Other candidiasis, cyanosis, hyperhidrosis, thoracic spine pain.

Contraindications

• Chronic renal failure with CrCl less than 5 ml/min/1.73 m² without hemodialysis;
• In children – severe renal failure (serum creatinine concentration greater than 2 mg/dl);
• Children under 3 months of age;
• Hypersensitivity to imipenem and/or cilastatin (other carbapenems and beta-lactam antibiotics) and to other components of the drug.

Use with caution in CNS diseases; anticonvulsant therapy with valproic acid (reduced efficacy of therapy); with CrCl less than 70 ml/min/1.73 m²; patients on hemodialysis; patients with a history of gastrointestinal diseases; pseudomembranous colitis; elderly age.

Use in Pregnancy and Lactation

Use of the drug during pregnancy is acceptable only if the potential benefit to the mother outweighs the potential risk to the fetus.

Both imipenem and cilastatin penetrate into breast milk in small amounts, so a decision should be made to discontinue breastfeeding during treatment with the drug.

Use in Renal Impairment

For adult patients with CrCl less than 70 ml/min/1.73 m² and/or lower body weight, the dose should be proportionally reduced.

Use of the drug in adult patients on hemodialysis is recommended only in cases where the benefit of treatment outweighs the potential risk of seizures.

Pediatric Use

Contraindicated in children under 3 months of age and in children with severe renal failure (serum creatinine concentration greater than 2 mg/dl).

Geriatric Use

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

Special Precautions

Not recommended for the treatment of meningitis.

Stains urine a reddish color (safe and should not be mistaken for hematuria).

The intravenous dosage form must not be used for intramuscular administration.

Before starting therapy, a thorough history should be taken regarding previous allergic reactions to beta-lactam antibiotics. If an allergic reaction occurs, the drug should be discontinued immediately.

Persons with a history of gastrointestinal diseases (especially colitis) have an increased risk of developing pseudomembranous colitis. With the use of the drug, both during administration and 2-3 weeks after cessation of treatment, diarrhea caused by Clostridium difficile (pseudomembranous colitis) may develop. In mild cases, discontinuation of treatment and the use of ion-exchange resins (cholestyramine, colestipol) is sufficient; in severe cases, replacement of fluid, electrolyte, and protein losses, and the administration of vancomycin or metronidazole is indicated. Drugs that inhibit intestinal peristalsis should not be used.

As with other beta-lactam antibiotics, Pseudomonas aeruginosa may develop resistance to imipenem quite rapidly. Therefore, during treatment, the susceptibility of Pseudomonas aeruginosa to the antibiotic should be periodically determined according to the clinical situation.

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

Antiepileptic drug therapy in patients with head trauma or a history of seizures should be continued throughout the entire period of treatment with the drug (to avoid CNS side effects).

To prevent the development of resistance and maintain the effectiveness of imipenem in clinical practice, the drug should be used only for the treatment of infections caused by microorganisms proven (or presumably) susceptible to imipenem.

Effect on ability to drive and operate machinery

Given the possibility of CNS side effects, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions. If CNS side effects occur, refrain from performing these activities.

Overdose

Symptoms dose-dependent side effects are intensified.

Treatment discontinue the drug, administer symptomatic and supportive therapy. Imipenem and cilastatin are removed by hemodialysis. However, the effectiveness of this procedure in case of drug overdose is unknown.

Drug Interactions

The drug is pharmaceutically incompatible with lactic acid (lactate) and must not be prepared using solvents containing it. However, the intravenous drug can be administered through the same infusion system as a solution containing lactate.

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

Concomitant use with ganciclovir increases the risk of generalized seizures. These drugs should not be used concomitantly, except in cases where the potential benefits outweigh the possible risk.

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

Use of the drug reduces the serum concentration of valproic acid, leading to a decrease in the effectiveness of anticonvulsant therapy, therefore monitoring of the plasma concentration of valproic acid is recommended during treatment.

The drug should not be mixed in the same syringe with other antibiotics, while simultaneous – isolated – administration with other antibiotics (aminoglycosides) is permitted.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years.

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.