Instructions for use TIENAM® (TIENAM)

Pharmacological properties of the drug Tienam

Tienam is indicated for the treatment of mixed infections caused by strains of aerobic and anaerobic microorganisms sensitive to it. Most pathogens of mixed infections are representatives of fecal microflora, microflora of the vagina, skin or oral cavity. Bacteroides fragilis is an anaerobic pathogen, most often isolated from patients with mixed infections and, as a rule, resistant to aminoglycosides, cephalosporins and penicillins, but sensitive to Thienam. Tienam is effective in the treatment of many infections caused by aerobic and anaerobic gram-positive and gram-negative microorganisms resistant to cephalosporins, including cefazolin, cefoperazone, cephalothin, cefoxitin, cefotaxime, moxalactam, cefamandole, ceftazidime and ceftriaxone. Most infections caused by pathogens resistant to aminoglycosides (gentamicin, amikacin, tobramycin) and/or penicillins (ampicillin, carbenicillin, penicillin-G, ticarcillin, piperacillin, azlocillin, mezlocillin) are sensitive to treatment with the drug. Tienam is not indicated for the treatment of meningitis. Thienam is a broad-spectrum β-lactam antibiotic, consisting of two components: imipenem, the first representative of a new class of β-lactam antibiotics, the thienamycins, and cilastatin sodium, a specific enzyme inhibitor that blocks the metabolism of imipenem in the kidneys and significantly increases the concentration of unchanged imipenem in the urinary tract. . The weight ratio of imipenem and cilastatin sodium in Tienam is 1:1. The class of thienamycin antibiotics, to which imipenem belongs, is characterized by a wider spectrum of bactericidal action compared to any of the antibiotics already studied. Thienam is a powerful inhibitor of bacterial cell wall synthesis and has a bactericidal effect against a wide range of gram-positive and gram-negative pathogenic aerobic and anaerobic microorganisms. Like modern cephalosporin and penicillin drugs, Thienam has a broad spectrum of action against gram-negative microorganisms, but unlike others, it is the only drug that has a pronounced effect against gram-positive microorganisms, previously sensitive only to the action of earlier narrow-spectrum β-lactam antibiotics. Thienam's spectrum of action includes Pseudomonas aeruginosa, Staphylococcus aureus, Enterococcus faecalis and Bacteroides fragilis , a diverse group of problematic pathogens usually resistant to other antibiotics. Tienam is resistant to bacterial β-lactamase, which makes it effective against many microorganisms such as Pseudomonas aeruginosa Serratia spp., and Enterobacter ., which are naturally resistant to most β-lactam antibiotics. The antibacterial spectrum of action of Tienam is wider than any other antibiotic already studied, and includes almost all clinically significant pathogenic microorganisms. Microorganisms for which Tienam is usually effective in vitro include: - Gram-negative aerobic bacteria: Achromobacter ., Acinetobacter (formerly Mima-Herellea ), Aeromonas hydrophila , Alcaligenes spp., Bordetella bronchicanis, Bordetella bronchiseptica, Bordetella pertussis, Brucella melitensis , Campylobacter , Capnocytophaga spp ., Citrobacter , Citrobacter diversus, Citrobacter freundii, Eikenella corrodens . , Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter cloacae, Escherichia coli, Gardnerella vaginalis, Haemophilus ducreyi, Haemophilus influenzae (including β-lactamase producing strains), Haemophilus parainfluenzae, Hafnia alvei , Klebsiella spp. (Klebsiella oxytoca, Klebsiella ozaenae, Klebsiella pneumoniae) , Moraxella spp., Morganella morganii (formerly Proteus morganii ), Neisseria gonorrhoeae (including penicillinase-producing strains), Neisseria meningitidis , Pasteurella spp., Pasteurella multocida, Plesiomonas shigelloide s , Proteus spp. ( Proteus mirabilis, Proteus vulgaris ), Providencia spp . ( Proteus alcalifaciens, Providencia rettgeri (formerly Proteus rettgeri ), Providencia stuartii ), Pseudomonas spp., including Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas pseudomallei, Pseudomonas putida, P seudomonas stutzeri, Xanthomonas maltophili a (formerly Pseudomonas maltophilia ) and some strains of Pseudomonas cepacia (generally insensitive to Tienam), Salmonella spp., Salmonella typhi, Serratia spp., Serratia proteamaculans (formerly Serratia liquefaciens ), Serratia marcescens , Shigella spp., Yersinia spp . (formerly Pasteurella ) , Yersinia enterocolitica, Yersinia pseudotuberculosis ; - gram-positive aerobic bacteria: Bacillus species, Enterococcus faecalis, Erysipelothrix rhusiopathiae, Listeria monocytogenes , Nocardia , Pediococcus species, Staphylococcus aureus (including penicillinase-forming strains), Staphylococcus epidermidis (including penicillinase-forming strains), Staphylococcus saprophyticus, Streptococcus agalact iae, Streptococcus group C, Streptococcus group G, Streptococcus pneumoniae, Streptococcus pyogenes, Viridans group streptococci (including α- and γ-hemolytic strains); Enterococcus faecium and some methicillin-resistant staphylococci are insensitive to Tienam; - gram-negative anaerobic bacteria: Bacteroides ( Bacteroides distasonis (formerly Bacteroides asaccharolyticus ), Bacteroides fragilis, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus ), Biophilia wadsworthia , Fusobacterium ( Fusobacterium necrophorum, Fusobacterium n ucleatum ), Porphyromonas asaccharolytica (formerly Bacteroides asacchrolyticus ), Prevotella bivia (formerly Bacteroides bivius ), Prevotella disiens (formerly Bacteroides disiens ), Prevotella intermedia (formerly Bacteroides vulgatus intermedius ), Prevotella melaninogenica (formerly Bacteroides melaninogenicus ), Veillonella spp .; - gram-positive anaerobic bacteria: Actinomyces , Bifidobacterium , Clostridium , Clostridium perfringens , Eubacterium Lactobacillus species, Mobiluncus species , Microaerophilic streptococcus , Peptococcus species , Peptostreptococcus , Propionibacterium (including P. acnes ); - others: Mycobacterium fortuitum, Mycobacterium smegmatis. in vitro studies indicate that imipenem has a synergistic effect with aminoglycoside antibiotics against some isolates of Pseudomonas aeruginosa . In healthy volunteers, intravenous infusion of Thienam at a dose of 500 mg over 20 minutes was accompanied by peak plasma levels of imipenem ranging from 21 to 58 mcg/ml. The half-life of imipenem in blood plasma was 1 hour. About 70% of the administered antibiotic was detected unchanged in the urine within 10 hours; further excretion of the drug in the urine was not observed. When using the drug Tienam according to the schedule every 6 hours, no accumulation of imipenem in the blood plasma or urine was detected in patients with normal renal function. Co-administration of Tienam and probenecid resulted in minimal increases in plasma levels and half-life of imipenem. When used alone, imipenem is metabolized in the kidneys by dihydropeptidase-1. Individual urinary recovery ranges from 5–40%, with an average of 15–20% in several studies. The binding of imipenem to human serum proteins is about 20%. Cilastatin, a specific inhibitor of the enzyme dehydropeptidase-1, effectively inhibits the metabolism of imipenem, so the simultaneous use of imipenem and cilastatin allows one to achieve therapeutic antibacterial levels of imipenem in urine and blood plasma. Peak cilastatin levels following a 20-minute IV infusion of Tienam 500 mg ranged from 21 to 55 mcg/mL. The half-life of cilastatin from the blood plasma is about 1 hour. About 70–80% of the dose of cilastatin is excreted unchanged in the urine within 10 hours after administration of the drug Tienam. After this, cilastatin is not detected in the urine. About 10% was determined as a metabolite of N-acetyl, which has an inhibitory effect on dehydropeptidase, which is comparable to that of the parent drug cilastatin. The combined use of Tienam and probenecid led to a 2-fold increase in plasma levels and an increase in the half-life of cilastatin, but did not affect the recovery of cilastatin in the urine. The binding of cilastatin to human serum proteins is about 40%.

Indications for use of the drug Tienam

Polymicrobial and mixed aerobic-anaerobic infections, primary therapy even before identifying the causative microorganism. Infections caused by microorganisms sensitive to the drug: – intra-abdominal infections; – lower respiratory tract infections; – gynecological infections; - urinary tract infections; – infections of bones and joints; – infections of the skin and soft tissues. Prophylaxis To prevent the occurrence of certain postoperative infections in patients undergoing surgery with or at risk of infection, or if these infections lead to particularly severe consequences.

Use of the drug Tienam

The total daily dose and method of administration of the drug Tienam are determined in terms of imipenem, taking into account the type and severity of the infection; the dose is distributed over several equal administrations, taking into account the degree of sensitivity of the pathogen(s), kidney function and body weight. Treatment: dosage regimen for adult patients with normal renal function Doses given in table. 1, is prescribed to patients with normal renal function (creatinine clearance 70 ml/min/1.73 m2) and a body weight of at least 70 kg. The dose should be reduced in patients with creatinine clearance ≤70 ml/min/1.73 m2 (Table 2) and/or with body weight ≤70 kg. In patients with significantly reduced body weight and/or moderate/severe renal impairment, dose reduction is particularly important. Most infections can be treated with a daily dose of 1–2 g (imipenem), divided into 3–4 doses. When treating moderate infections, you can also use a daily dose schedule of 1 g (imipenem) 2 times a day. In the case of infections caused by less sensitive organisms, the daily dose of Thienam can be increased to a maximum of 4 g (imipenem) per day or 50 mg/kg per day, whichever dose is lower. Each dose not exceeding 500 mg of Thienam (imipenem) for intravenous use should be administered over 20–30 minutes. Each dose above 500 mg (imipenem) should be administered over at least 40–60 minutes. If the patient experiences nausea during the infusion, the rate of drug administration should be slowed down. Table 1 Dosing frequency in adult patients with normal renal function and a body weight of 70 kg or more*

*In patients weighing ≤70 kg, the prescribed dose should be proportionally reduced; **if it is necessary to prescribe low doses of the drug, it is recommended to use the drug in lower doses.

Due to the high antimicrobial effectiveness of the drug Tienam, it is not recommended to exceed the daily dose of 50 mg/kg/day or 4 g per day, whichever dose is lower. However, patients with cystic fibrosis and unimpaired renal function are prescribed up to 80 mg/kg of the drug per day, divided into several administrations, provided that they do not exceed 4 g per day. Tienam is successfully used as monotherapy in patients with cancer and weakened immunity with confirmed or suspected infections, such as sepsis. Treatment: dosages for adults with impaired renal function To determine the dose for patients with impaired renal function:

1. Select (see Table 1) the total daily dose, taking into account the characteristics of the infection.
2. Select the required dose reduction regimen (Table 2), taking into account the dose selected in the Table. 1 daily dose and creatinine clearance indicators for this patient.

Table 2 Scheme for reducing doses of Tienam for intravenous administration in adult patients with impaired renal function and a body weight of 70 kg or more*

*In patients weighing ≤70 kg, the prescribed dose should be proportionally reduced; **if it is necessary to prescribe low doses of the drug, it is recommended to use the drug in lower doses.

When used at a dose of 500 mg in patients with a creatinine clearance of 6–20 ml/min/1.73 m2, the risk of seizures significantly increases. Thiene for IV administration should not be prescribed to patients with creatinine clearance ≤5 ml/min/1.73 m2, unless these patients undergo hemodialysis within the next 48 hours. Hemodialysis When treating patients whose creatinine clearance is ≤5 ml/min/1.73 m2 and who undergo dialysis, doses recommended for use in patients with a creatinine clearance of 6–20 ml/min/1.73 m2 are used. Both imipenem and cilastatin are eliminated during hemodialysis. The patient must be administered Tienam immediately after the hemodialysis session and then administered every 12 hours after its completion. Patients on hemodialysis, and especially those with central nervous system disorders, need careful monitoring; It is recommended to prescribe Tienam to such patients only if the expected effect exceeds the probable risk of seizures (see PECULIARITIES OF APPLICATION). Currently, there is insufficient data regarding the use of Tienam in patients on peritoneal dialysis, therefore it is not recommended to use it for treatment in this category of patients. Creatinine and blood urea nitrogen levels may not accurately reflect the status of kidney function in older adults. In such patients, it is recommended to determine creatinine clearance for appropriate dose selection. Prevention: doses for adults To prevent postoperative infections, adults should be administered intravenously 1000 mg of Tienam during induction of anesthesia and 1000 mg after 3 hours. In case of high-risk surgery (for example, during surgery on the colon or rectum), two additional doses should be administered doses of 500 mg 8 and 16 hours after induction of anesthesia. There are no sufficient data regarding the prophylactic use of Tienam IV in patients with creatinine clearance ≤70 ml/min/1.73 m2. Treatment: doses for children (from 3 months of age) For children, the following dosage regimen is recommended:

• in children weighing 40 kg, the same doses are used as for adults;
• in children weighing ≤40 kg, doses are used at the rate of 15 mg/kg at 6-hour intervals.

The total daily dose should not exceed 2 g. It is not recommended to use the drug in children under 3 months of age or with impaired renal function (serum creatinine 2 mg/dL) due to insufficient clinical data. Tienam is not recommended for the treatment of meningitis. If meningitis is suspected, appropriate antibiotics should be prescribed. Tienam can be used to treat sepsis in children in the absence of suspicion of meningitis. Preparation of solution for intravenous administration

Preparation of Tienam solution in 20 ml bottles The contents of the bottle should be suspended and brought to 100 ml with the appropriate solution for infusion. It is recommended to add about 10 ml of the appropriate solution for infusion (solvents used: isotonic sodium chloride solution; 5–10% aqueous dextrose solution; 5% dextrose solution and 0.9% NaCl solution; 5% dextrose solution and 0.45% NaCl solution; 5% dextrose solution and 0.225% NaCl solution; 5% dextrose solution and 0.15 KCl solution; mannitol 5 and 10% solution p) to the bottle. Shake well and add the resulting suspension to the container with solution for infusion. Warning : the suspension is not a ready-made solution for infusion. Repeat the procedure, adding again 10 ml of solution for infusion so that the entire contents of the bottle are transferred to the solution for infusion. The resulting mixture must be shaken. until it becomes transparent. Solutions are stored at room temperature (25 °C) for 4 hours or at a temperature not exceeding 4 °C for 24 hours.

Release form and composition

Thienam is available in the form of a powder for the preparation of a solution for infusion: the color of the powder is from white to light yellow (in glass bottles with a capacity of 20 ml, 10 bottles in a plastic tray covered with plastic film, in a cardboard box 1 pallet; in glass bottles with a capacity of 20 ml , 25 bottles in a plastic cell tray, 1 tray in a cardboard box; glass bottles with a capacity of 115 ml, 5 bottles in a cardboard box complete with five connecting tubes).

Composition of 1 bottle of powder:

• active ingredients: sterile imipenem – 500 mg, sterile cilastatin sodium – 500 mg;
• auxiliary components: sterile sodium bicarbonate – 20 mg.

Side effects of the drug Thienam

Tienam is generally well tolerated. Adverse reactions rarely require discontinuation of treatment and are usually mild and transient; Severe side effects are rare. Among the known side effects, local ones are most often observed. Local manifestations (the same for different routes of administration): erythema, pain and infiltrates at the sites of drug administration, thrombophlebitis. Allergic reactions/skin manifestations : anaphylactic reactions, rash, pruritus, urticaria, erythema multiforme, Stevenson-Johnson syndrome, angioedema, toxic epidermal necrolysis (rare), exfoliative dermatitis (rare), candidiasis, fever (including drug-induced fever). Reactions from the gastrointestinal tract : nausea, vomiting, diarrhea, pigmentation of teeth and/or tongue. As with almost all other broad-spectrum antibiotics, pseudomembranous colitis may occasionally occur. Reactions from the hematopoietic system: eosinophilia, leukopenia, neutropenia, including agranulocytosis, thrombocytopenia, thrombocytosis, decreased hemoglobin levels, pancytopenia and increased prothrombin time. Some patients may have a positive direct Coombs test. Reactions from liver function: increased levels of transaminases, bilirubin and/or alkaline phosphatase; liver failure (rare), hepatitis (rare) and fulminant hepatitis (very rare). Reactions from renal function: oliguria/anuria, polyuria, acute renal failure (rare). It is difficult to assess whether Thienam affects renal function, since, as a rule, other factors predisposing to impaired renal function and the development of azotemia are simultaneously present. Increases in serum creatinine and blood urea nitrogen levels were detected. A change in the color of the urine has been noted, which does not pose any threat and should not be confused with hematuria. Reactions from the nervous system: when using the drug Tienam, like other β-lactam antibiotics, side effects such as myoclonus, mental disorders (including hallucinations), confusion and convulsions, paresthesia, and encephalopathy develop. Reactions from the senses: hearing loss, change in taste. Patients with granulocytopenia Nausea and/or vomiting caused by the use of Tienam occurs more often in patients with granulocytopenia than without it.

Special instructions for the use of Tienam

Some clinical and laboratory data are known that indicate partial cross-allergenicity of the drug Tienam and other β-lactam antibiotics, penicillins and cephalosporins. Severe reactions (including anaphylaxis) have been reported with most β-lactam antibiotics. Before starting drug therapy, the patient's medical history should be carefully examined for the presence of a hypersensitivity reaction to β-lactam antibiotics. If an allergic reaction develops during use of the drug, the drug must be discontinued and appropriate measures taken. The development of pseudomembranous colitis has been reported as a complication with the use of almost all antibiotics; its forms can range from mild to life-threatening. In this regard, antibiotics should be prescribed with caution to patients with a history of gastrointestinal diseases, especially colitis. It is important to remember the possibility of developing pseudomembranous colitis if a patient develops diarrhea during antibiotic treatment. Although available research evidence suggests that a toxin produced by Clostridium difficile is the primary cause of antibiotic-associated colitis, other possible etiological factors should be kept in mind. CNS . As with therapy with other β-lactam antibiotics, CNS side effects such as myoclonus, confusion or convulsions have been described with Tienam, especially in cases where recommended doses have been exceeded depending on renal function and body weight. Typically, such disorders were noted in patients with damage to the central nervous system (brain injury or history of seizures) and/or in patients with impaired renal function, in whom accumulation of the drug in the body is possible. Therefore, in such patients it is necessary to carefully follow the recommended doses and dosage regimen. Therapy with anticonvulsants should be considered in patients with a history of seizures. If focal tremor, myoclonus or seizures occur during treatment with the drug, patients should undergo a neurological examination with the prescription of anticonvulsant therapy, if such treatment has not been prescribed before. If symptoms of central nervous system disorders persist, the dose of Tienam should be reduced or the drug should be discontinued. Thienam is not indicated for the treatment of patients with creatinine clearance ≤20 ml/min/1.73 m2, unless hemodialysis is required after 48 hours. In patients receiving hemodialysis, Tienam is recommended only in cases where the positive results of treatment outweigh the potential risk of developing seizures. During pregnancy and breastfeeding. Use during pregnancy has not been sufficiently studied, so the drug can be prescribed only if the expected benefit to the mother outweighs the possible risk to the fetus. Imipenem passes into breast milk. If it is necessary to use the drug in the mother, breastfeeding should be stopped. Children. Due to insufficient clinical data, it is not recommended to use Thienam in children under 3 months of age and in children with impaired renal function (serum creatinine 2 mg/dL). The ability to influence reaction speed when driving vehicles and working with other mechanisms. Given the risk of side effects such as myoclonus, hallucinations, confusion and convulsions, you should avoid driving and operating other machinery when using the drug.

Contraindications

Absolute:

• renal dysfunction with creatinine clearance (creatinine clearance) less than 5 ml/min;
• children up to three months of age;
• impaired renal function in children (serum creatinine more than 2 mg/dl);
• hypersensitivity to the ingredients of the drug, as well as other beta-lactam antibiotics, cephalosporins and penicillins.

Relative (Tienam is used with caution):

• renal dysfunction (creatinine clearance less than 70 ml/min);
• hemodialysis;
• history of gastrointestinal diseases;
• pseudomembranous colitis;
• diseases of the central nervous system.

Interactions of the drug Tienam

In patients receiving ganciclovir and Tienam simultaneously for intravenous infusion, generalized seizures were detected. These drugs should not be coadministered unless the expected benefit outweighs the potential risk. During post-marketing studies, decreased plasma levels of valproic acid have been reported when administered concomitantly with carbapenems, and in some cases, sudden onset seizures have been reported. When imepenem is used concomitantly with valproic acid, it is necessary to carefully monitor the level of valproic acid in the blood plasma.

Use for renal impairment

Doses of imipenem for intravenous infusion in patients with impaired renal function and a body weight of 70 kg or more

.

Tienam should not be used in patients with CC less than 5 ml/min/1.73 m2

, unless hemodialysis is prescribed every 48 hours. Both imipenem and cilastatin are eliminated from the circulation during hemodialysis.
Tienam should be prescribed after a hemodialysis session and at 12-hour intervals from the completion of the procedure. Currently, there is insufficient data to make recommendations for the use of Thienam in patients on peritoneal dialysis.