Imipenem/cilastatin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Imipenem/Cilastatin

Composition:

Active substances: imipenem and cilastatin sodium;

1 vial contains imipenem monohydrate equivalent to 500 mg of imipenem, cilastatin sodium equivalent to 500 mg of cilastatin;

Excipient: sodium bicarbonate.

Pharmaceutical form. Powder for solution for infusion.

Main physicochemical characteristics: powder from white to light yellow in color.

Pharmacotherapeutic group.

Antibacterials for systemic use. Carbapenems. ATC code J01D H51.

Pharmacological properties.

Pharmacodynamics.

The drug consists of two components: imipenem, the first representative of a new class of β-lactam antibiotics – the thienamycins, and sodium cilastatin, a specific inhibitor of the enzyme that blocks imipenem metabolism in the kidneys and significantly increases the concentration of unchanged imipenem in the urinary tract. The weight ratio of imipenem to sodium cilastatin in the drug is 1:1.

The class of thienamycin antibiotics, to which imipenem belongs, is characterized by a broader spectrum of potent bactericidal activity than that provided by any of the previously studied antibiotics.

Imipenem/Cilastatin is indicated for the treatment of mixed infections caused by susceptible strains of aerobic and anaerobic bacteria. Imipenem/Cilastatin has demonstrated efficacy in treating many infections caused by aerobic and anaerobic gram-positive and gram-negative bacteria resistant to cephalosporins, including cefazolin, cefoperazone, cephalothin, cefoxitin, cefotaxime, moxalactam, cefamandole, ceftazidime, and ceftriaxone. A large number of infections caused by pathogens resistant to aminoglycosides (gentamicin, amikacin, tobramycin) and/or penicillins (ampicillin, carbenicillin, penicillin-G, ticarcillin, piperacillin, azlocillin, mezlocillin) are also amenable to treatment with Imipenem/Cilastatin.

Imipenem/Cilastatin is not indicated for the treatment of meningitis.

Imipenem/Cilastatin is a potent inhibitor of bacterial cell wall synthesis and exerts bactericidal activity against a broad spectrum of gram-positive and gram-negative, aerobic and anaerobic pathogenic microorganisms.

Imipenem/Cilastatin, along with newer cephalosporins and penicillins, has a broad spectrum of activity against gram-negative species, but its distinguishing feature is high activity against gram-positive species, which previously was observed only with narrow-spectrum β-lactam antibiotics. The drug's spectrum of activity includes Pseudomonas aeruginosa, Staphylococcus aureus, Enterococcus faecalis, and Bacteroides fragilis—a diverse and clinically challenging group of pathogens typically resistant to other antibiotics.

Imipenem/Cilastatin is effective against a large number of microorganisms such as Pseudomonas aeruginosa, species of Serratia and Enterobacter, which are inherently resistant to most β-lactam antibiotics.

The antimicrobial spectrum of the drug is broader than that of any other known antibiotic and encompasses all clinically significant pathogenic microorganisms. Microorganisms generally susceptible to Imipenem/Cilastatin in vitro include:

Gram-negative aerobic bacteria

Species of Achromobacter, species of Acinetobacter (formerly Mima-Herellea), Aeromonas hydrophila, species of Alcaligenes, Bordetella bronchicanis, Bordetella bronchiseptica, Bordetella pertussis, Brucella melitensis, Burkholderia pseudomallei (formerly Pseudomonas pseudomallei), Burkholderia stutzeri (formerly Pseudomonas stutzeri), species of Campylobacter, species of Capnocytophaga, species of Citrobacter, Citrobacter koseri (formerly Citrobacter diversus), Citrobacter freundii, Eikenella corrodens, species of Enterobacter, Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter cloacae, Escherichia coli, Gardnerella vaginalis, Haemophilus ducreyi, Haemophilus influenzae (including β-lactamase-producing strains), Haemophilus parainfluenzae, Hafnia alvei, species of Klebsiella, Klebsiella oxytoca, Klebsiella ozaenae, Klebsiella pneumoniae, species of Moraxella, Morganella morganii (formerly Proteus morganii), Neisseria gonorrhoeae (including penicillinase-producing strains), Neisseria meningitidis, species of Pasteurella, Pasteurella multocida, Plesiomonas shigelloides, species of Proteus, Proteus mirabilis, Proteus vulgaris, species of Providencia, Providencia alcalifaciens, Providencia rettgeri (formerly Proteus rettgeri), Providencia stuartii, species of Pseudomonas*, Pseudomonas fluorescens, Pseudomonas putida, Pseudomonas aeruginosa, species of Salmonella, Salmonella typhi, species of Serratia, Serratia proteamaculans (formerly Serratia liquefaciens), Serratia marcescens, species of Shigella, species of Yersinia (formerly Pasteurella), Yersinia enterocolitica, Yersinia pseudotuberculosis.

*Stenotrophomonas maltophilia (formerly Xanthomonas maltophilia, formerly Pseudomonas maltophilia) and strains of Burkholderia cepacia (formerly Pseudomonas cepacia) are generally not susceptible to Imipenem/Cilastatin.

Gram-positive aerobic bacteria

Species of Bacillus, Enterococcus faecalis, Erysipelothrix rhusiopathiae, Listeria monocytogenes, species of Nocardia, species of Pediococcus, Staphylococcus aureus (including penicillinase-producing strains), Staphylococcus epidermidis (including penicillinase-producing strains), Staphylococcus saprophyticus, Streptococcus agalactiae, Streptococcus group C, Streptococcus group G, Streptococcus pneumoniae, Streptococcus pyogenes, Viridans Streptococci (including α- and γ-hemolytic strains). Enterococcus faecium and certain methicillin-resistant staphylococci are not susceptible to Imipenem/Cilastatin.

Gram-negative anaerobic bacteria

Species of Bacteroides, Bacteroides distasonis, Bacteroides fragilis, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Bilophila wadsworthia, species of Fusobacterium, Fusobacterium necrophorum, Fusobacterium nucleatum, Porphyromonas asaccharolytica (formerly Bacteroides asaccharolyticus), Prevotella bivia (formerly Bacteroides bivius), Prevotella disiens (formerly Bacteroides disiens), Prevotella intermedia (formerly Bacteroides intermedius), Prevotella melaninogenica (formerly Bacteroides melaninogenicus), species of Veillonella.

Gram-positive anaerobic bacteria

Species of Actinomyces, species of Bifidobacterium, species of Clostridium, Clostridium perfringens, species of Eubacterium, species of Lactobacillus, species of Mobiluncus, Microaerophilic streptococcus, species of Peptococcus, species of Peptostreptococcus, species of Propionibacterium (including P. acnes).

Others

Mycobacterium fortuitum, Mycobacterium smegmatis.

In vitro studies indicate that imipenem acts synergistically with aminoglycosides against certain isolates of Pseudomonas aeruginosa.

Pharmacokinetics.

In healthy volunteers, after a 20-minute intravenous infusion of 500 mg of the drug, the peak plasma concentration of imipenem ranged from 21 to 58 mcg/mL. The elimination half-life of imipenem in plasma was 1 hour. Approximately 70% of the administered antibiotic was recovered unchanged in urine within 10 hours, with no further excretion observed. When administered every 6 hours, no accumulation of imipenem in plasma or urine was observed in patients with normal renal function. Concomitant administration of the drug and probenecid resulted in minimal increases in plasma concentration and half-life of imipenem. When administered alone, imipenem is metabolized in the kidneys by dehydropeptidase-I. Urinary recovery ranged from 5 to 40%, averaging 15–20% in several studies. The protein binding of imipenem to human serum proteins is approximately 20%.

Cilastatin is a specific inhibitor of dehydropeptidase-I enzyme and effectively inhibits imipenem metabolism; thus, the concomitant administration of imipenem and cilastatin allows achieving therapeutic antibacterial levels of imipenem in urine and plasma. The peak plasma concentration of cilastatin after a 20-minute intravenous infusion of 500 mg of the drug ranged from 21 to 55 mcg/mL. The elimination half-life of cilastatin in plasma is approximately 1 hour. Approximately 70–80% of the cilastatin dose is excreted unchanged in urine within 10 hours after administration of the drug. After this period, cilastatin was not detected in urine. About 10% was found as the N-acetyl metabolite, which has inhibitory activity against dehydropeptidase comparable to that of cilastatin. Concomitant administration of the drug and probenecid resulted in a doubling of plasma concentration and elimination half-life of cilastatin, but did not affect its urinary recovery.

The protein binding of cilastatin to human serum proteins is approximately 40%.

Renal impairment

After a single 250 mg/250 mg intravenous dose, the area under the concentration-time curve (AUC) for imipenem increased by 1.1, 1.9, and 2.7 times in patients with mild (creatinine clearance (CrCL) 50–80 mL/min/1.73 m²), moderate (CrCL 30–<50 mL/min/1.73 m²), and severe (CrCL <30 mL/min/1.73 m²) renal impairment, respectively, compared to patients with normal renal function (CrCL >80 mL/min/1.73 m²). The AUC for cilastatin increased by 1.6, 2, and 6.2 times, respectively, in patients with mild, moderate, and severe renal impairment compared to those with normal renal function. After a single 250 mg/250 mg intravenous dose administered 24 hours after hemodialysis, the AUC for imipenem and cilastatin was 3.7 and 16.4 times higher, respectively, compared to patients with normal renal function. After intravenous administration, urinary excretion, renal clearance, and plasma clearance of imipenem and cilastatin decrease with declining renal function. Dose adjustment is necessary for patients with impaired renal function.

Hepatic impairment

The pharmacokinetics of imipenem in patients with hepatic impairment have not been established. Due to the limited extent of hepatic metabolism of imipenem, hepatic impairment is not expected to affect its pharmacokinetics. Therefore, dose adjustment is not recommended for patients with hepatic impairment.

Children

The mean clearance and volume of distribution for imipenem were approximately 45% higher in children (aged 3 months to 14 years) compared to adults. The AUC for imipenem after administration of a 15/15 mg/kg dose of imipenem/cilastatin in children was approximately 30% higher than the AUC in adults receiving a 500 mg/500 mg dose. At a higher dose, exposure after administration of 25/25 mg/kg imipenem/cilastatin in children was 9% higher compared to exposure in adults receiving a 1000 mg/1000 mg dose.

Elderly patients

In healthy elderly volunteers (aged 65 to 75 years with normal renal function for their age), the pharmacokinetics of a single 500 mg/500 mg intravenous dose of Imipenem/Cilastatin administered over 20 minutes were consistent with expected results in patients with mild renal impairment, for whom no dose adjustments are considered necessary. The mean elimination half-lives of imipenem and cilastatin in plasma were 91 ± 7 minutes and 69 ± 15 minutes, respectively. Repeated dosing did not affect the pharmacokinetics of imipenem or cilastatin, and no accumulation of imipenem/cilastatin was observed.

Clinical characteristics.

Indications.

Treatment of infections in adults and children aged 1 year and older caused by microorganisms susceptible to the drug:

• intra-abdominal infections;
• lower respiratory tract infections (severe pneumonia, including hospital-acquired and ventilator-associated pneumonia);
• intrapartum and postpartum infections;
• complicated urinary and genital tract infections;
• complicated skin and soft tissue infections;
• bone and joint infections;
• septicemia;
• endocarditis.

The drug may be used in the treatment of patients with febrile neutropenia likely caused by bacterial infection.

Treatment of patients with bacteremia associated or likely associated with any of the above-mentioned infections.

Contraindications.

Hypersensitivity to any component of the drug, other carbapenem drugs, or acute hypersensitivity reactions (e.g., anaphylactic reactions, severe skin reactions) to other β-lactam antibiotics (e.g., penicillins or cephalosporins).

Interaction with other medicinal products and other forms of interaction.

Generalized seizures have been observed in patients who received ganciclovir concomitantly with intravenous Imipenem/Cilastatin. These drugs may be used together only if the expected benefit outweighs the potential risk.

Reduced plasma levels of valproic acid have been reported when co-administered with carbapenems, and sudden seizures have been observed in some cases. Therefore, concomitant use of imipenem and valproic acid/sodium valproate is not recommended. Consideration should also be given to using alternative antibacterial or anticonvulsant therapies (see section "Special precautions for use").

Oral anticoagulants

Concomitant use of antibiotics with warfarin may enhance its anticoagulant effects. Numerous reports have documented increased anticoagulant effects of oral anticoagulants, including warfarin, in patients receiving antibiotics concomitantly. The risk may vary depending on the type of infection, age, and overall condition of the patient, making it difficult to assess the exact role of the antibiotic in increasing the international normalized ratio (INR). Frequent monitoring of INR is recommended during and after concomitant use of antibiotics with oral anticoagulants.

Concomitant administration of the drug and probenecid resulted in minimal increases in plasma concentration and elimination half-life of imipenem. Renal excretion of active (unmetabolized) imipenem decreased to approximately 60% of the dose when the drug was administered with probenecid. Concomitant use of the drug and probenecid doubled plasma levels and elimination half-life of cilastatin, but had no effect on renal excretion of cilastatin.

Special precautions for use.

There are known clinical and laboratory data indicating partial cross-allergenicity between the drug Imipenem/Cilastatin and other β-lactam antibiotics, penicillins, and cephalosporins. Severe reactions (including anaphylaxis) have been observed with the use of most β-lactam antibiotics. Such reactions are most likely to occur in individuals with a history of sensitivity to multiple allergens. Prior to initiating therapy with this drug, a careful patient history should be obtained regarding previous hypersensitivity reactions to carbapenems, penicillins, cephalosporins, other β-lactam antibiotics, and other allergens. If an allergic reaction occurs during treatment, the drug should be discontinued and appropriate measures taken. Severe anaphylactic reactions require immediate treatment.

Liver function should be closely monitored during treatment with imipenem/cilastatin due to the risk of hepatotoxicity (elevated transaminase levels, liver failure, and fulminant hepatitis).

Patients with pre-existing liver disease require monitoring of liver function during treatment with imipenem/cilastatin. Dose adjustment is not required.

A positive direct or indirect Coombs test may occur during treatment with imipenem/cilastatin.

Prior to any empirical therapy, the antibacterial spectrum of imipenem/cilastatin should be considered, especially in life-threatening conditions. In addition, caution should be exercised due to limited susceptibility of certain pathogens (e.g., those associated with skin and soft tissue infections) to imipenem/cilastatin. The use of imipenem/cilastatin is appropriate for treating these types of infections only if the specific pathogen has been documented and is known to be susceptible, or when there are very strong reasons to believe that the most likely pathogen(s) are amenable to such treatment. Concomitant use of this agent against methicillin-resistant Staphylococcus aureus (MRSA) may be indicated when MRSA infection is suspected or confirmed in approved indications. Concomitant use of an aminoglycoside may be indicated when Pseudomonas aeruginosa infection is suspected or confirmed in approved indications.

Concomitant administration of imipenem/cilastatin and valproic acid/sodium valproate is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Antibiotic-associated colitis and pseudomembranous colitis have been reported as complications of nearly all antibiotics; the severity may range from mild to life-threatening. Therefore, antibiotics should be used cautiously in patients with a history of gastrointestinal disorders, particularly colitis. Pseudomembranous colitis should be considered in any patient who develops diarrhea during or after antibiotic therapy. Discontinuation of imipenem/cilastatin and initiation of specific treatment for Clostridium difficile should be considered. Antiperistaltic agents should not be prescribed.

The drug is not recommended for the treatment of meningitis.

Imipenem and cilastatin accumulate in patients with impaired renal function. If the dose is not adjusted according to renal function, adverse reactions affecting the central nervous system (CNS) may occur.

As with other β-lactam antibiotics, adverse effects on the CNS such as myoclonus, confusion, or seizures have been reported with the use of Imipenem/Cilastatin, particularly when recommended doses based on renal function and body weight have been exceeded. Such disorders have usually been observed in patients with pre-existing CNS disorders (e.g., brain injury or history of seizures) and/or in patients with impaired renal function, in whom drug accumulation may occur. Therefore, strict adherence to recommended dosing and treatment regimens is essential, especially in such patients. Anticonvulsant therapy should be continued in patients with a history of seizures.

Particular attention should be paid to neurological symptoms or seizures in children with known risk factors for seizures and in children receiving concomitant treatment with anticonvulsant medications.

If focal tremor, myoclonus, or seizures occur during treatment, patients should undergo neurological evaluation and anticonvulsant therapy should be initiated if not already prescribed. If CNS adverse effects persist, the dose of Imipenem/Cilastatin should be reduced or the drug discontinued entirely.

Imipenem/Cilastatin is not indicated for use in patients with a creatinine clearance of <15 mL/min, except when hemodialysis will be performed within 48 hours. For patients undergoing hemodialysis, Imipenem/Cilastatin should be used only if the expected benefits outweigh the potential risk of seizures.

The drug contains 20 mg of sodium, which should be taken into account when administering it to patients on a sodium-restricted (low-salt) diet.

Use during pregnancy or breastfeeding.

Pregnancy.

Adequate and well-controlled studies on the use of this medicinal product in pregnant women have not been conducted.

Reproductive toxicity was observed in studies conducted on pregnant monkeys. The potential risk to humans is unknown. Imipenem/Cilastatin should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding period.

Imipenem and cilastatin are excreted in small amounts in breast milk. If use of the drug is necessary, the benefit of breastfeeding for the infant should be weighed against the potential risk associated with the drug's use.

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect of the medicinal product on the ability to drive or operate machinery have not been conducted. However, certain adverse effects (such as hallucinations, drowsiness, dizziness, and vertigo) associated with the use of the drug may affect the ability of some patients to drive or operate machinery.

Administration and Dosage

Dosage

Dosage recommendations for the drug refer to the amount of imipenem/cilastatin to be administered.

The daily dose of the drug is determined based on the type and severity of infection and is divided into several equal doses, taking into account the susceptibility of the causative pathogen(s) and the patient's renal function.

Adults and adolescents

Recommended dosage regimen for patients with normal renal function (creatinine clearance ≥ 90 mL/min):

• 500 mg/500 mg every 6 hours, or
• 1000 mg/1000 mg every 8 hours or every 6 hours.

For the treatment of infections caused by less susceptible bacterial species (such as Pseudomonas aeruginosa) or very severe infections (e.g., febrile neutropenia), a dosage of 1000 mg/1000 mg every 6 hours is recommended.

Dosage should be reduced in patients with creatinine clearance ≤ 90 mL/min (see table).

The maximum daily dose should not exceed 4000 mg/4000 mg per day.

Renal impairment

To determine the reduced dosage for adult patients with renal impairment:

1. Determine the total daily dose (i.e., 2000/2000, 3000/3000, or 4000/4000 mg) typically administered to patients with normal renal function.
2. Select the appropriate reduced-dose regimen (see table) according to the patient's creatinine clearance. Information on infusion duration is provided below in the section "Administration".

Creatinine clearance (ml/min)	Total daily dose 2000 mg	Total daily dose 3000 mg	Total daily dose 4000 mg
≥ 90 (normal)	500 every 6 hours	1000 every 8 hours	1000 every 6 hours
reduced dose (mg) for patients with renal impairment
< 90 – ≥ 60	400 every 6 hours	500 every 6 hours	750 every 8 hours
< 60 – ≥ 30	300 every 6 hours	500 every 8 hours	500 every 6 hours
< 30 – ≥ 15	200 every 6 hours	500 every 12 hours	500 every 12 hours

Patients with creatinine clearance <15 ml/min

Imipenem/Cilastatin should not be administered to patients with creatinine clearance <15 ml/min unless they are scheduled to undergo hemodialysis within the next 48 hours.

Patients undergoing hemodialysis

For treatment of patients with creatinine clearance <15 ml/min who are undergoing hemodialysis, doses recommended for patients with creatinine clearance of 15–29 ml/min should be used (see table).

Both imipenem and cilastatin are removed during hemodialysis. Imipenem/Cilastatin should be administered to the patient immediately after the hemodialysis session and then every 12 hours following its completion. Patients undergoing hemodialysis, particularly those with underlying central nervous system (CNS) disorders, require close monitoring; Imipenem/Cilastatin should be prescribed to such patients only if the expected benefit outweighs the potential risk of seizures (see section "Special precautions").

Currently, there is insufficient data on the use of the drug in patients undergoing peritoneal dialysis; therefore, its use is not recommended for treating this patient group.

Hepatic impairment

Dosage adjustment is not required in patients with hepatic dysfunction.

Elderly patients

Dosage adjustment is not required in elderly patients with normal renal function.

Children aged 1 year and older

For children aged >1 year, the recommended dose is 15/15 or 25/25 mg/kg every 6 hours.

For treatment of infections likely or confirmed to be caused by less susceptible bacterial species (such as Pseudomonas aeruginosa) or severe infections (e.g., febrile neutropenic patients), a dose of 25/25 mg/kg every 6 hours is recommended.

Children under 1 year of age

The drug is not recommended for children under 1 year of age due to insufficient clinical data.

Children with renal impairment

The drug is not recommended for children with renal impairment (serum creatinine >2 mg/dL) due to insufficient clinical data.

Method of administration

Before administration, Imipenem/Cilastatin must be reconstituted and then diluted.

Doses not exceeding 500 mg/500 mg for intravenous infusion should be administered over 20–30 minutes. Doses exceeding 500 mg/500 mg should be administered over 40–60 minutes. If nausea occurs during infusion, the infusion rate should be reduced.

Reconstitution

Imipenem/Cilastatin for intravenous infusion is supplied as a sterile powder in vials containing 500 mg imipenem equivalent and 500 mg cilastatin equivalent.

Each vial is intended for single use only.

The contents of one vial should be transferred to 100 ml of an appropriate infusion solution (0.9% sodium chloride solution). Under exceptional circumstances, when 0.9% sodium chloride solution cannot be used for clinical reasons, 5% glucose may be used as the diluent.

It is recommended to add approximately 10 ml of 0.9% sodium chloride solution to the vial.

Mix well and transfer the resulting suspension to an infusion container.

WARNING: THE SUSPENSION IS NOT A READY-TO-USE INFUSION SOLUTION.

Repeat the procedure by adding another 10 ml of infusion solution to ensure complete transfer of the vial contents into the infusion solution. Mix thoroughly until the solution becomes clear.

The concentration of the reconstituted solution after this procedure is approximately 5 mg/ml of both imipenem and cilastatin.

Diluted solutions should be used immediately. The time interval between the start of reconstitution and completion of intravenous infusion should not exceed 2 hours.

Children.

Due to insufficient clinical data, Imipenem/Cilastatin is not recommended for children under 1 year of age and for children with renal impairment (serum creatinine >2 mg/dL) (see section "Dosage and method of administration").

Overdose.

Symptoms of overdose are consistent with the drug's adverse reaction profile and may include seizures, confusion, tremor, nausea, vomiting, hypotension, and bradycardia.

There is no specific information on the treatment of overdose. The drug can be removed by hemodialysis; however, the effectiveness of this procedure in overdose has not been established. Treatment is symptomatic.

Adverse Reactions.

Clinical studies have reported the following most common systemic adverse reactions possibly related to treatment: nausea (2.0%), diarrhea (1.8%), vomiting (1.5%), rash (0.9%), fever (0.5%), arterial hypotension (0.4%), seizures (0.4%), dizziness (0.3%), pruritus (0.3%), urticaria (0.2%), somnolence (0.2%). Local adverse reactions included: phlebitis/thrombophlebitis (3.1%), injection site pain (0.7%), injection site erythema (0.4%), and venous induration (0.2%). Additionally, increased serum transaminase and alkaline phosphatase levels were observed.

The adverse reactions listed below and their frequencies are based on clinical study results. Adverse events are categorized by system organ class and frequency: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1000 to <1/100), rare (>1/10,000 to <1/1000), very rare (<1/10,000), and frequency not known (cannot be estimated from available data).

Infections and infestations: rare – pseudomembranous colitis, candidiasis; very rare – gastroenteritis.

Blood and lymphatic system disorders: common – eosinophilia; uncommon – pancytopenia, neutropenia, leukopenia, thrombocytopenia, thrombocytosis; rare – agranulocytosis; very rare – hemolytic anemia, bone marrow suppression.

Immune system disorders: rare – anaphylactic reactions.

Psychiatric disorders: uncommon – psychiatric disturbances, including hallucinations and confusion.

Nervous system disorders: uncommon – seizures, myoclonic activity, dizziness, somnolence; rare – encephalopathy, paresthesia, focal tremor, taste disturbance; very rare – worsening of severe myasthenia, headache; frequency not known – agitation, dyskinesia.

Ear and labyrinth disorders: rare – hearing loss; very rare – vertigo, tinnitus.

Cardiac disorders: very rare – cyanosis, tachycardia, palpitations.

Vascular disorders: common – thrombophlebitis; uncommon – arterial hypotension; very rare – flushing.

Respiratory, thoracic and mediastinal disorders: very rare – dyspnea, hyperventilation, pharyngeal pain.

Gastrointestinal disorders: common – diarrhea, vomiting, nausea (nausea and/or vomiting associated with the drug occur more frequently in patients with granulocytopenia than in those without granulocytopenia receiving the drug); rare – discoloration of teeth and/or tongue; very rare – hemorrhagic colitis, abdominal pain, heartburn, glossitis, lingual papillae hypertrophy, increased salivation.

Hepatobiliary disorders: rare – liver failure, hepatitis; very rare – fulminant hepatitis.

Skin and subcutaneous tissue disorders: common – rash (e.g., exanthematous); uncommon – urticaria, pruritus; rare – toxic epidermal necrolysis, angioneurotic edema (Quincke's edema), Stevens-Johnson syndrome, polymorphic erythema, exfoliative dermatitis; very rare – hyperhidrosis, skin texture changes.

Musculoskeletal and connective tissue disorders: very rare – polyarthralgia, thoracic spine pain.

Renal and urinary disorders: rare – acute renal failure, oliguria/anuria, polyuria, change in urine color (harmless, should not be confused with hematuria). The impact of Imipenem/Cilastatin on renal function is difficult to assess, as predisposing factors for prerenal azotemia or worsening renal function were usually present.

Reproductive system and breast disorders: very rare – genital pruritus.

General disorders and administration site conditions: uncommon – fever, local pain and induration at injection site, erythema at injection site; very rare – chest discomfort, asthenia/weakness.

Investigations: common – increased serum transaminases, increased serum alkaline phosphatase; uncommon – positive direct Coombs test, prolonged prothrombin time, decreased hemoglobin, increased serum bilirubin, increased serum creatinine, increased blood urea nitrogen.

In studies involving 178 children aged > 3 months, adverse reactions were reported that were entirely similar to those observed in adult patients.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after marketing authorization. This allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging, out of reach of children, at a temperature not exceeding 25°C.

Incompatibilities.

Imipenem/Cilastatin for intravenous administration is chemically incompatible with lactates (salts of lactic acid) and must not be diluted with solvents containing lactates. However, Imipenem/Cilastatin may be administered through the same intravenous system used for lactate solution infusions.

Imipenem/Cilastatin for intravenous administration must not be mixed with other medicinal products except those specified in the "Reconstitution" section.

Packaging.

10 vials per cardboard box.

Prescription category. Prescription only.

Manufacturer. JW Pharmaceutical Corporation.

Manufacturer's address and location of operations.

56 Hanji 1-gil, Songak-eup, Dangjin-si, Chungcheongnam-do, Republic of Korea.

Date of last revision. 21.09.2021.