Imibacid

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT IMIBACID (IMIBACID)

Composition:

Active substances: imipenem and cilastatin;

1 vial contains 500 mg of imipenem and 500 mg of cilastatin (as sodium cilastatin);

Excipient: sodium hydrogen carbonate.

Pharmaceutical form. Powder for solution for infusion.

Main physicochemical properties: powder from white or almost white to light yellow color.

Pharmacotherapeutic group. Antibacterials for systemic use. Carbapenems. Imipenem and cilastatin. ATC code J01DH51.

Pharmacological Properties.

Pharmacodynamics.

Imibacid consists of two components: imipenem, the first representative of a new class of β-lactam antibiotics – the thienamycins, and cilastatin, a specific inhibitor of the enzyme responsible for blocking the metabolism of imipenem in the kidneys, significantly increasing the concentration of unchanged imipenem in the urinary tract. Cilastatin has no intrinsic antibacterial activity and does not affect the antibacterial activity of imipenem.

The weight ratio of imipenem to cilastatin in the Imibacid preparation is 1:1.

The thienamycin class of antibiotics, to which imipenem belongs, is characterized by a broad spectrum of potent bactericidal activity.

Imipenem is a powerful inhibitor of bacterial cell wall synthesis and exerts bactericidal activity against a wide range of susceptible pathogenic microorganisms. Imipenem has demonstrated efficacy in the treatment of numerous 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 significant 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 responsive to treatment with imipenem. Imipenem is not indicated for the treatment of meningitis.

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

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

Microorganisms generally susceptible in vitro to Imibacid include:

Gram-negative aerobic bacteria

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

* Stenotrophomonas maltophilia (formerly Xanthomonas maltophilia, formerly Pseudomonas maltophilia) and Burkholderia cepacia (formerly Pseudomonas cepacia) strains are generally not susceptible to Imibacid.

Gram-positive aerobic bacteria

Bacillus species
Enterococcus faecalis
Erysipelothrix rhusiopathiae
Listeria monocytogenes
Nocardia species
Pediococcus species
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 some methicillin-resistant staphylococci are not susceptible to Imibacid.

Gram-negative anaerobic bacteria

Bacteroides species
Bacteroides distasonis
Bacteroides fragilis
Bacteroides ovalus
Bacteroides thetaiotaomicron
Bacteroides uniformis
Bacteroides vulgatus
Bilophila wadsworthia
Fusobacterium species
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)
Veilonella spp.

Gram-positive anaerobic bacteria

Actinomyces species
Bifidobacterium species
Clostridium species
Clostridium perfringens
Eubacterium species
Lactobacillus species
Mobiluncus species
Microaerophilic streptococcus
Peptococcus species
Peptostreptococcus species
Propionibacterium species (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, a 20-minute intravenous infusion of imipenem/cilastatin at a dose of 500 mg/500 mg resulted in peak plasma concentrations of imipenem ranging from 21 to 58 µg/mL. The elimination half-life of imipenem in plasma was approximately 1 hour. Approximately 70% of the administered antibiotic was recovered unchanged in urine within 10 hours, with no further excretion observed thereafter. When imipenem/cilastatin was administered every 6 hours, no accumulation of imipenem in plasma or urine was observed in patients with normal renal function. Concomitant administration of imipenem/cilastatin and probenecid caused minimal increases in plasma levels and elimination half-life of imipenem. When administered alone, imipenem is metabolized in the kidneys by dehydropeptidase-I. Renal recovery ranged from 5 to 40%, averaging 15–20% across several studies. The protein binding of imipenem to human serum proteins is approximately 20%.

Cilastatin, a specific inhibitor of dehydropeptidase-I, effectively inhibits the metabolism of imipenem. Therefore, the simultaneous administration of imipenem and cilastatin enables the achievement of therapeutic antibacterial levels of imipenem in urine and plasma. Peak plasma concentrations of cilastatin after a 20-minute intravenous infusion of imipenem/cilastatin at a dose of 500 mg/500 mg ranged from 21 to 55 µg/mL. The elimination half-life of cilastatin in plasma is approximately 1 hour. Approximately 70–80% of the administered dose of cilastatin is excreted unchanged in urine within 10 hours after administration of imipenem/cilastatin. After this period, cilastatin was not detected in urine. Approximately 10% of cilastatin was recovered as the N-acetyl metabolite, which has inhibitory activity against dehydropeptidase comparable to that of the parent compound. Concomitant administration of imipenem/cilastatin and probenecid resulted in a doubling of plasma levels and elimination half-life of cilastatin, but did not affect its urinary excretion.

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

Renal Impairment

After a single intravenous dose of imipenem/cilastatin 250 mg/250 mg, the area under the concentration-time curve (AUC) of 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 of 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 intravenous dose of imipenem/cilastatin 250 mg/250 mg administered 24 hours after hemodialysis, the AUC of imipenem and cilastatin was 3.7 and 16.4 times higher, respectively, compared to patients with normal renal function. Renal excretion, renal clearance, and plasma clearance of imipenem and cilastatin after intravenous administration decrease proportionally with declining renal function. Dose adjustment is required for patients with impaired renal function.

Hepatic Impairment

The pharmacokinetics of imipenem in patients with hepatic impairment has not been studied. Due to the limited extent of hepatic metabolism of imipenem, hepatic dysfunction is not expected to significantly affect its pharmacokinetics. Therefore, dose adjustment in patients with hepatic impairment is not recommended.

Children

The average clearance and volume of distribution of imipenem were approximately 45% higher in children (aged 3 months to 14 years) compared to adults. The AUC of imipenem after administration of a 15/15 mg/kg dose of imipenem/cilastatin in children was approximately 30% higher than 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 the AUC 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 20-minute intravenous infusion of imipenem/cilastatin 500 mg/500 mg were consistent with those expected in patients with mild renal impairment, for whom dose adjustment is not considered necessary. Mean elimination half-lives of imipenem and cilastatin in plasma were 91 ± 7 minutes and 69 ± 15 minutes, respectively. Repeated administration 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);
• Intra- and postpartum infections;
• Complicated urinary tract infections;
• Complicated skin and soft tissue infections;
• Bone and joint infections;
• Septicemia;
• Endocarditis.

The drug Imibacid may be used for the treatment of patients with neutropenia accompanied by fever, likely caused by a bacterial infection.

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

Official recommendations regarding appropriate use of antibacterial agents should be taken into account.

Contraindications.

• Hypersensitivity to imipenem, cilastatin, or to any other component of the drug;
• Hypersensitivity to other carbapenems;
• Severe hypersensitivity reactions (e.g., anaphylactic reaction, severe skin reactions) to other β-lactam antibiotics (e.g., penicillins or cephalosporins).

Interaction with other medicinal products and other types of interactions.

Ganciclovir. Generalized seizures have been reported in patients receiving ganciclovir concomitantly with intravenous imipenem/cilastatin. These drugs should be used together only if the expected benefit outweighs the potential risks.

Valproic acid/sodium valproate. There have been reports of decreased plasma levels of valproic acid below the therapeutic range when co-administered with carbapenems, which may lead to inadequate seizure control and sudden seizures. Therefore, concomitant use of imipenem and valproic acid/sodium valproate is not recommended. Alternative antibacterial or anticonvulsant therapy should be considered (see section "Special warnings and precautions for use").

Oral anticoagulants. Concomitant use of antibiotics with warfarin may potentiate its anticoagulant effect. The risk may vary depending on the type of infection, age, and general condition of the patient, making it difficult to assess the impact of the antibiotic on INR (International Normalized Ratio) elevation. Frequent monitoring of INR is recommended during and for some time after concomitant use of antibiotics with oral anticoagulants (see section "Special warnings and precautions for use").

Probenecid. Concomitant administration of imipenem/cilastatin and probenecid resulted in minimal increases in imipenem plasma concentration and plasma half-life of imipenem. Renal excretion of active (unmetabolized) imipenem decreased to approximately 60% of the dose when imipenem/cilastatin was administered with probenecid. Concomitant use of imipenem/cilastatin and probenecid doubled the plasma levels and half-life of cilastatin, but did not affect the urinary excretion of cilastatin.

Children. Interaction studies have been conducted only in adults.

Special precautions for use.

General recommendations.

When selecting imipenem/cilastatin for treatment of a specific patient, the appropriateness of using carbapenems should be evaluated by considering factors such as the severity of infection, prevalence of resistance to other suitable antibacterial agents, and the likelihood of pathogens being resistant to carbapenems.

Hypersensitivity reactions.

There is some clinical and laboratory evidence indicating partial cross-allergy between imipenem/cilastatin and other β-lactam antibiotics, including penicillins and cephalosporins. Serious and sometimes fatal hypersensitivity reactions (anaphylactic reactions) have been reported in patients receiving beta-lactam therapy. These reactions occur more frequently in individuals with a history of sensitivity to multiple allergens. Prior to initiating therapy with this medicinal product, a careful assessment of previous hypersensitivity reactions to carbapenems, penicillins, cephalosporins, other beta-lactams, and other allergens should be performed (see section "Contraindications"). If any allergic reaction occurs, administration of the drug should be discontinued immediately and appropriate measures should be taken. Serious anaphylactic reactions require immediate emergency treatment.

Liver.

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 should have liver function monitored during treatment with imipenem/cilastatin. Dose adjustment is not required (see section "Dosage and administration").

Effect on serological test results.

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

Antibacterial spectrum.

Before initiating 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 specific pathogens (e.g., those associated with bacterial 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 to imipenem/cilastatin, or when there are very strong reasons to believe that the most likely pathogen(s) are susceptible to this treatment.

Concomitant use of this agent against methicillin-resistant Staphylococcus aureus (MRSA) may be indicated when MRSA involvement 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 (see section "Indications").

Interaction with valproic acid.

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").

Clostridium difficile.

Antibiotic-associated colitis and pseudomembranous colitis, ranging in severity from mild to life-threatening, have been reported with the use of imipenem/cilastatin and nearly all other antibiotics. Therefore, it is important to consider this diagnosis in all patients who develop diarrhea during or after antibiotic therapy (see section "Adverse reactions"). Discontinuation of imipenem/cilastatin therapy and initiation of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be prescribed.

Antibiotics should be prescribed with caution in patients with gastrointestinal disorders, particularly those with a history of colitis.

Meningitis.

Imipenem/cilastatin is not recommended for the treatment of meningitis.

Renal function impairment.

Imipenem/cilastatin accumulates in patients with impaired renal function. Adverse reactions affecting the central nervous system (CNS) may occur if the dose is not adjusted according to renal function (see section "Dosage and administration" and subsection "CNS" below).

CNS.

Adverse CNS reactions such as myoclonia, confusion, or seizures have been reported, particularly when recommended doses adjusted for renal function and body weight are exceeded. Such reactions 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, where drug accumulation may occur. Therefore, strict adherence to recommended dosing regimens and treatment schedules is strongly advised for these patients (see section "Dosage and administration"). Anticonvulsant therapy should be continued in patients with a history of seizure disorders.

Special attention should be paid to neurological symptoms or seizures in children with known risk factors for seizures or who are receiving concomitant medications that lower the seizure threshold.

If focal tremor, myoclonus, or seizures occur during treatment, patients should undergo neurological evaluation and anticonvulsant therapy should be initiated if not already in place. If CNS symptoms persist, the dose of imipenem/cilastatin should be reduced or its administration discontinued.

Patients with creatinine clearance (CrCl) ≤ 5 ml/min/1.73 m² should not receive imipenem/cilastatin unless hemodialysis is initiated within 48 hours. Imipenem/cilastatin is recommended for patients undergoing hemodialysis only when the benefit outweighs the potential risk of seizures (see section "Dosage and administration").

Sodium.

The Imibacid 500 mg/500 mg medicinal product contains 37.6 mg of sodium (1.6 mg-eq), equivalent to 1.9% of the WHO recommended maximum daily intake of sodium, which is 2 g for adults. This should be taken into account for patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding.

Pregnancy.

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

Reproductive toxicity was observed in studies of imipenem/cilastatin in pregnant monkeys. The potential risk to humans is unknown. Imibacid should be used during pregnancy only if the expected benefit to the pregnant woman outweighs the potential risk to the fetus.

Lactation.

Imipenem and cilastatin are excreted in small amounts in breast milk. Therefore, it is unlikely that a breastfed infant would receive significant doses of the drug. However, if treatment with the medicinal product is necessary, breastfeeding should be discontinued.

Fertility.

Data regarding the potential effect of imipenem/cilastatin treatment on male or female fertility are lacking.

Ability to affect reaction rate when driving or operating machinery.

Due to the risk of adverse effects such as hallucinations, somnolence, dizziness, and vertigo, driving and operating vehicles or machinery should be avoided during treatment with this medicinal product.

Administration and dosage.

The recommended doses for the drug Imibacid refer to the amount of imipenem/cilastatin to be administered.

The daily dose of Imibacid should be determined based on the type and severity of infection, the pathogen(s) isolated, taking into account renal function and body weight; the dose should be divided into several equal administrations.

Adult patients with normal renal function

Doses for patients with normal renal function (creatinine clearance > 70 mL/min/1.73 m²) and body weight of at least 70 kg:

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

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

Dosage should be reduced in patients:

• with creatinine clearance ≤ 70 mL/min/1.73 m² and/or
• with body weight less than 70 kg.

Dose reduction based on body weight is particularly important in patients with body weight significantly below 70 kg and/or moderate to severe renal impairment.

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

The dose for patients with body weight less than 70 kg should be calculated using the formula:

Actual body weight (kg) × standard dose

70 (kg)

Adult patients with impaired renal function

To determine the reduced dose for adult patients with impaired renal function:

1. Determine the total daily dose (i.e., 2000/2000, 3000/3000, or 4000/4000 mg) normally administered to patients with normal renal function.
2. Select the appropriate reduced dosing regimen (see Table 1) according to the patient's creatinine clearance and duration of infusion (see section "Administration").

Table 1

Imibacid dosing for adult patients
with impaired renal function and body weight of 70 kg or more*

* For patients with body weight less than 70 kg, the recommended dose should be proportionally reduced.

** When using the 500 mg/500 mg dose in patients with CrCl of 6–20 mL/min/1.73 m², the risk of seizures significantly increases.

Imibacid for intravenous administration should not be administered to patients with CrCl ≤ 5 mL/min/1.73 m² unless they are scheduled to undergo hemodialysis within the next 48 hours.

Hemodialysis

For treatment of patients with CrCl ≤ 5 mL/min/1.73 m² who are on hemodialysis, use the doses recommended for patients with CrCl of 6–20 mL/min/1.73 m² (see Table 1).

Both imipenem and cilastatin are eliminated during hemodialysis. Imibacid should be administered to the patient immediately after completion of a hemodialysis session, and then the drug should be administered every 12 hours thereafter. Patients undergoing hemodialysis, particularly those with underlying CNS disorders, require close monitoring; Imibacid should be prescribed to such patients only if the anticipated benefit outweighs the potential risk of seizures (see section "Special precautions").

Currently, there is insufficient data on the use of imipenem/cilastatin in patients undergoing peritoneal dialysis; therefore, its use is not recommended for treatment of this patient population.

Hepatic impairment

Dose adjustment is not required in patients with hepatic dysfunction.

Geriatric patients

Dose 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 organisms (such as Pseudomonas aeruginosa) and for severe infections (e.g., febrile neutropenic patients), a dose of 25/25 mg/kg every 6 hours is recommended.

The use of the drug is not recommended in children with impaired renal function (serum creatinine > 2 mg/dL) due to insufficient clinical data.

Administration method

A single dose of Imibacid for intravenous use not exceeding 500 mg/500 mg should be administered over 20–30 minutes. A single dose exceeding 500 mg/500 mg should be administered over 40–60 minutes. If nausea occurs during infusion, the infusion rate should be reduced.

Preparation of solution for intravenous administration

Imibacid for intravenous infusion is supplied as a sterile powder in vials containing 500 mg of imipenem equivalent and 500 mg of cilastatin equivalent.

Sodium bicarbonate is included in Imibacid formulation as a buffer, ensuring the resulting solution has a pH between 6.5 and 8.5. These pH variations are not clinically significant provided the solution is prepared and stored according to the instructions provided. Imibacid for intravenous administration contains 37.5 mg of sodium (1.6 mEq).

The sterile powder of Imibacid should be reconstituted as specified in Table 2. The resulting solution should be shaken until a clear solution is obtained. Variation in solution color from colorless to yellow does not affect the drug's activity.

Table 2

Preparation of Imibacid solution for intravenous administration

Preparation of Imibacid solution in 30 ml vials

The contents of the vial must be suspended and diluted to 100 ml with an appropriate infusion solution.

It is recommended to add approximately 10 ml of 0.9% sodium chloride solution to the vial. Under exceptional circumstances, when 0.9% sodium chloride solution cannot be used for clinical reasons, 5% glucose may be used as the solvent.

Shake well and transfer the resulting suspension to a container with infusion solution.

WARNING: THE SUSPENSION IS NOT THE FINAL 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. The resulting mixture should be shaken until it becomes clear.

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

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

Children.

Due to insufficient clinical data, Imibacid is not recommended for use in children under 1 year of age and in children with impaired renal function (serum creatinine > 2 mg/dl) (see section "Dosage and administration").

Overdose.

Symptoms of overdose may be consistent with the profile of adverse reactions and may include seizures, confusion, tremor, nausea, vomiting, hypotension, and bradycardia.

There is no specific information on the treatment in case of imipenem/cilastatin overdose. Imipenem/cilastatin is removed by hemodialysis. However, the benefit of this procedure in overdose has not been established. Treatment is symptomatic.

Adverse reactions

The most common systemic adverse reactions that were possibly related to treatment with imipenem/cilastatin were nausea (2%), 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%).

The most common local adverse reactions were phlebitis/thrombophlebitis (3.1%), injection site pain (0.7%), injection site erythema (0.4%), and venous induration (0.2%).

Elevations in serum transaminase and alkaline phosphatase levels were also observed.

Adverse reactions are presented in Table 3 by system organ class and frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated based on available data).

Table 3

During clinical trials of imipenem/cilastatin involving 178 children aged ≥ 3 months, adverse reactions were reported that were entirely similar to those observed in adult patients.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 4 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Incompatibilities.

Imibacid for intravenous administration is chemically incompatible with lactates (salts of lactic acid), and must not be reconstituted with solvents containing lactates. However, Imibacid may be administered through the same intravenous line used for lactate-containing solutions.

Imibacid for intravenous administration must not be mixed with other medicinal products except those specified in the section "Preparation of solution for intravenous administration".

Packaging. 1 vial of powder per carton.

Prescription status. Prescription only.

Manufacturer. Public Joint-Stock Company "Scientific and Production Center "Borshchagovskiy Chemical and Pharmaceutical Plant".

Manufacturer's address and location of manufacturing site. 17, Miru Street, Kyiv, 03134, Ukraine.