Cilpen

INSTRUCTIONS for medical use of the medicinal product CILPEN (CILPEN)

Composition:

Active substances: imipenem; cilastatin.

One vial contains imipenem (as imipenem monohydrate) 500 mg and cilastatin (as cilastatin sodium) 500 mg;

Excipient: sodium hydrogen carbonate.

Pharmaceutical form. Powder for solution for infusion.

Main physico-chemical properties: powder ranging from white to almost white or slightly yellowish.

Pharmacotherapeutic group. Antibacterials for systemic use. Carbapenems. Imipenem and enzyme inhibitor. ATC code J01D H51.

Pharmacological properties.

Pharmacodynamics.

Cilpen consists of two components: imipenem and sodium cilastatin in a 1:1 weight ratio.

Imipenem, also known as N-formimidoyl-thienamycin, is a semisynthetic derivative of thienamycin, the original compound produced by the filamentous bacterium Streptomyces cattleya.

Imipenem exhibits bactericidal activity by inhibiting the synthesis of the bacterial cell wall in Gram-positive and Gram-negative bacteria through binding to penicillin-binding proteins (PBPs).

Sodium cilastatin is a competitive, reversible, and specific inhibitor of renal dehydropeptidase-I, the enzyme responsible for the metabolism and inactivation of imipenem. It has no intrinsic antibacterial activity and does not affect the antibacterial activity of imipenem.

Pharmacokinetic/pharmacodynamic (PK/PD) relationship

As with other β-lactam antibiotics, the parameter that best correlates with efficacy for imipenem is the duration of time during which the concentration exceeds the minimum inhibitory concentration (T > MIC).

Mechanism of resistance

Resistance to imipenem may be due to the following mechanisms:

• reduced permeability of the outer membrane of Gram-negative bacteria (due to decreased porin production);
• active efflux of imipenem from the cell via efflux pumps;
• reduced affinity of imipenem for PBPs;
• imipenem is stable against hydrolysis by most β-lactamases, including penicillinases and cephalosporinases produced by Gram-positive and Gram-negative bacteria, except for relatively rare β-lactamases capable of hydrolyzing carbapenems. Organisms resistant to other carbapenems generally exhibit co-resistance to imipenem. There is no target-site cross-resistance between imipenem and quinolone antibiotics, aminoglycosides, macrolides, or tetracyclines.

Breakpoints

The European Committee on Antimicrobial Susceptibility Testing (EUCAST) has established the following minimum inhibitory concentration (MIC) breakpoints for imipenem (v.10.0, 2020-01-01):

Microorganism group	Minimum inhibitory concentration (mg/l)
	Susceptible ≤	Resistant >
Enterobacterales	2	4
Enterobacterales 1 (Morganella morganii, Proteus spp. and Providencia spp.)	0.001	4
Pseudomonas spp.	0.001	4
Acinetobacter spp.	2	4
Staphylococcus spp.	Based on susceptibility data to cefoxitin
Enterococcus spp.	0.001	4
Streptococcus A, B, C, G	Based on susceptibility data to benzylpenicillin
Streptococcus pneumoniae	2	2
Viridans group streptococci	2	2
Haemophilus influenzae	2	2
Moraxella catarrhalis 2	2	2
Gram-positive anaerobic microorganisms, except Clostridioides difficile	2	4
Gram-negative anaerobic microorganisms	2	4
Burkholderia pseudomallei	2	2
Non–strain-related breakpoints3	2	4

1 Naturally low activity of imipenem against Morganella morganii, Proteus spp., and Providencia spp. requires high imipenem exposure.

2 Resistant isolates are rare or have not yet been reported. Results of microbial identification and antimicrobial susceptibility testing for any isolate should be confirmed, and the isolate should be sent to a reference laboratory.

3 Breakpoints not associated with any strain have been established primarily based on PK/PD data and independently of the MIC distribution for specific species. These breakpoints are intended for use only for species not listed in the summary of strain-associated breakpoints or in the footnotes.

Susceptibility

The prevalence of acquired resistance may vary geographically and over time for individual species; therefore, local information on resistance should be obtained, especially when treating severe infections. Expert advice should be sought if local resistance prevalence renders the efficacy of the drug questionable for treating at least some types of infections.

Usually susceptible species:

Gram-positive aerobic microorganisms

Enterococcus faecalis, Staphylococcus aureus (methicillin-susceptible)*, Staphylococcus coagulase-negative (methicillin-susceptible), Staphylococcus epidermidis, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus viridans group.

Gram-negative aerobic microorganisms

Acinetobacter spp., Citrobacter spp., Citrobacter freundii, Enterobacter spp., Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Gardnerella vaginalis, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella spp., Klebsiella oxytoca, Klebsiella pneumoniae, Moraxella catarrhalis, Morganella morganii, Proteus vulgaris, Providencia rettgeri, Pseudomonas aeruginosa, Serratia spp., including S. marcescens.

Gram-positive anaerobic microorganisms

Bifidobacterium spp., Clostridium spp., Clostridium perfringens**, Eubacterium spp., Peptococcus spp., Peptostreptococcus spp.**, Propionibacterium spp.

Gram-negative anaerobic microorganisms

Bacteroides spp., including B. fragilis, Bacteroides fragilis group, Fusobacterium spp., Porphyromonas asaccharolytica, Prevotella spp., Veillonella spp.

Species for which acquired resistance may be problematic:

Gram-negative aerobic microorganisms

Acinetobacter calcoaceticus baumannii complex, Pseudomonas aeruginosa.

Naturally resistant species:

Gram-positive aerobic microorganisms

Enterococcus faecium.

Gram-negative aerobic microorganisms

Some strains of Burkholderia cepacia complex, Legionella spp., Stenotrophomonas maltophilia (previously Xanthomonas maltophilia, previously Pseudomonas maltophilia).

Others:

Chlamydia spp., Chlamydophila spp., Mycoplasma spp., Ureoplasma urealyticum.

* All methicillin-resistant staphylococci are resistant to imipenem/cilastatin.

** Non-species-related breakpoints according to EUCAST are applied.

Pharmacokinetics.

Imipenem.

Absorption. In healthy volunteers, following a 20-minute intravenous infusion of 500 mg of the medicinal product Cilpen, peak plasma concentrations of imipenem ranged from 21 to 58 µg/mL. The mean peak plasma concentration of imipenem after administration of a 500 mg/500 mg dose was 39 µg/mL. Plasma levels of imipenem declined to less than 1 µg/mL within 4–6 hours.

Distribution. The binding of imipenem to human serum proteins is approximately 20%.

Metabolism. When administered alone, imipenem is metabolized in the kidneys by dehydropeptidase-I. Individual recovery in urine ranged from 5% to 40%, averaging 15–20% in several studies.

Cilastatin is a specific inhibitor of the enzyme dehydropeptidase-I. It effectively inhibits the metabolism of imipenem; therefore, co-administration of imipenem and cilastatin allows achieving therapeutic antibacterial levels of imipenem in urine and plasma.

Elimination. The elimination half-life (t½) of imipenem in plasma is 1 hour. Approximately 70% of the administered antibiotic was recovered unchanged in urine within 10 hours, with no further urinary excretion observed. The concentration of imipenem in urine during the 8-hour period following administration of a 500 mg/500 mg dose exceeded 10 µg/mL. The remainder of the dose was excreted in urine as antibacterially inactive metabolites, and fecal elimination of imipenem was virtually negligible.

With repeated administration of the medicinal product Cilpen every 6 hours, no accumulation of imipenem in plasma or urine was observed in patients with normal renal function.

Cilastatin.

Absorption. Peak plasma concentrations of cilastatin after a 20-minute intravenous infusion of a 500 mg dose of the drug ranged from 21 to 55 µg/mL. The mean peak plasma concentration of cilastatin after administration of a 500 mg/500 mg dose was 42 µg/mL.

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

Metabolism and elimination. The elimination half-life of cilastatin in plasma is approximately 1 hour. About 70–80% of the cilastatin dose is excreted unchanged in urine within 10 hours after administration. After this period, cilastatin was not detected in urine. Approximately 10% was found as the N-acetyl metabolite, which exhibits inhibitory activity against dehydropeptidase comparable to that of cilastatin. Dehydropeptidase-I activity in the kidneys returns to normal shortly after cilastatin is eliminated from the bloodstream.

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. Urinary excretion, renal clearance, and plasma clearance of imipenem and cilastatin decrease with declining renal function following intravenous administration of Cilpen. Dose adjustment is required for patients with impaired renal function (see section "Dosage and administration").

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 (see section "Dosage and administration").

Children. Mean clearance and volume of distribution of imipenem were approximately 45% higher in children (aged 3 months to 14 years) compared to adults. The area under the concentration-time curve (AUC) for imipenem after administration of a 15/15 mg/kg dose of imipenem/cilastatin in children was approximately 30% higher than exposure 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 20-minute intravenous dose of imipenem/cilastatin 500 mg/500 mg were consistent with expectations for patients with mild renal impairment, for whom any dose adjustments are considered unnecessary. Mean elimination half-lives of imipenem and cilastatin in plasma were 91±7 minutes and 69±15 minutes, respectively. Repeated administration had no effect on the pharmacokinetics of imipenem or cilastatin, and no accumulation of imipenem/cilastatin was observed (see section "Dosage and administration").

Clinical characteristics.

Indications.

Treatment of infections in adults and children aged 1 year and older caused by microorganisms sensitive 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 a bacterial infection.

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

Contraindications.

Hypersensitivity to any component of the medicinal product, 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 types of interactions.

Generalized seizures have been observed in patients who received ganciclovir concomitantly with intravenous imipenem/cilastatin. These drugs should be co-administered only if the expected benefit outweighs the potential risk.

Reduced plasma levels of valproic acid to concentrations that may fall below therapeutic levels have been reported when valproic acid is used concomitantly with carbapenems. Decreased valproic acid levels may lead to inadequate seizure control; therefore, concomitant use of imipenem and valproic acid/sodium valproate is not recommended, and consideration should be given to 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 general 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 imipenem/cilastatin 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 administered with probenecid. Simultaneous administration of the drug and probenecid doubled the plasma levels and t½ of cilastatin, but had no effect on the urinary excretion of cilastatin.

Special precautions.

General recommendations. When selecting imipenem/cilastatin for treatment of an individual patient, the appropriateness of using a carbapenem antibiotic should be considered, taking into account factors such as severity of infection, prevalence of resistance to other appropriate antibacterial agents, and the risk of selecting for treatment of infections caused by carbapenem-resistant bacteria.

Hypersensitivity. Severe, and sometimes fatal, hypersensitivity reactions (including anaphylaxis) have been reported in patients receiving β-lactam antibiotics. These reactions are most likely to occur in individuals with a history of sensitivity to multiple allergens. Prior to initiating therapy with the drug, a careful patient history should be obtained regarding previous hypersensitivity reactions to carbapenems, penicillins, cephalosporins, other β-lactam antibiotics, and other allergens (see section "Contraindications"). If an allergic reaction occurs during administration of the drug, it should be discontinued immediately. Serious anaphylactic reactions require emergency treatment.

Liver function. 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.

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

Antibacterial spectrum. The antibacterial spectrum of imipenem/cilastatin should be considered prior to any empirical therapy, especially in conditions that are life-threatening. Additionally, caution is warranted due to limited susceptibility of certain pathogens (e.g., those associated with skin and soft tissue infections) to imipenem/cilastatin. Use of imipenem/cilastatin is appropriate for treatment of these types of infections only when 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 susceptible to this 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 (see section "Indications").

Clostridium difficile. Antibiotic-associated colitis and pseudomembranous colitis, with severity ranging from mild to life-threatening, have been reported with imipenem/cilastatin, as with nearly all other antibiotics. It is important to consider this diagnosis in patients who develop diarrhea during or after receiving imipenem/cilastatin (see section "Adverse reactions"). Discontinuation of imipenem/cilastatin therapy and initiation of specific treatment for Clostridioides difficile should be considered. Antiperistaltic agents should not be prescribed.

Meningitis. The drug is not recommended for the treatment of meningitis.

Renal function impairment. Imipenem/cilastatin accumulates in patients with impaired renal function. If the dose is not appropriately reduced according to renal function, adverse reactions affecting the central nervous system may occur (see "Dosage and administration" and below).

Central nervous system (CNS). As with other β-lactam antibiotics, CNS adverse effects such as myoclonia, confusion, or seizures have been reported with the use of Cilpen. These effects are particularly likely when recommended doses—determined according to renal function and body weight—are exceeded. Such disorders usually occur 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 caution is required regarding neurological symptoms or seizures in children with known risk factors for seizures or who are receiving concomitant medications that lower seizure threshold.

If focal tremor, myoclonia, or seizures occur during treatment, patients should undergo neurological evaluation and be started on anticonvulsant therapy if not already receiving it. If CNS adverse effects persist, the dose of Cilpen should be reduced or the drug discontinued entirely.

Cilpen is not indicated for use in patients with a creatinine clearance of < 15 mL/min, except in cases where hemodialysis will be performed within 48 hours. For patients undergoing hemodialysis, Cilpen should only be used if the expected therapeutic benefit outweighs the potential risk of seizures (see section "Dosage and administration").

Excipients. The medicinal product contains 37.6 mg of sodium (1.6 mg-eq.), which should be taken into account when administering it to patients on a controlled sodium (salt-free) diet.

Use during pregnancy or breastfeeding.

Pregnancy. Adequate and well-controlled studies of the drug in pregnant women have not been conducted.

Reproductive toxicity was observed in studies in pregnant monkeys. The potential risk to humans is unknown. Cilpen should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus.

Breastfeeding period. Imipenem and cilastatin are excreted in small amounts into breast milk. Therefore, it is unlikely that a breastfed infant would receive significant amounts of the drug. If use of the drug is necessary, the benefit of breastfeeding for the infant should be weighed against the potential risk associated with drug exposure.

Fertility. There are no data regarding the potential impact of imipenem/cilastatin treatment on male or female fertility.

Effect on ability to drive and use machines.

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

Dosage and Administration

The dosage recommendations for the medicinal product Cilpen below refer to the amount of imipenem/cilastatin to be administered.

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

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

Dosage should be reduced if creatinine clearance is < 90 mL/min (see Table 1).

Maximum daily dose should not exceed 4000 mg / 4000 mg per day.

Renal impairment

To determine the reduced dosage 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 dosage regimen (see Table 1) according to the patient's creatinine clearance. Information on infusion duration is provided below in the section "Administration".

Table 1

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 impaired renal function
< 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. Cilpen 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 1).

Both imipenem and cilastatin are removed during hemodialysis. The drug should be administered immediately after the hemodialysis session and then every 12 hours thereafter. Patients undergoing hemodialysis, especially those with underlying central nervous system (CNS) disorders, require close monitoring; Cilpen 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 in this patient population is not recommended.

Hepatic impairment. Dose adjustment is not required in patients with hepatic dysfunction.

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

Children aged 1 year and older. The recommended dose for children aged >1 year is 15/15 or 25/25 mg/kg/dose administered every 6 hours.

For the treatment of infections likely or confirmed to be caused by less susceptible organisms (such as Pseudomonas aeruginosa) and 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 use of the drug is not recommended in children under 1 year of age due to insufficient clinical data.

Children with renal impairment. 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. The drug must be reconstituted and then diluted before administration.

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

Reconstitution. Each vial is intended for single use only.

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

At the first step, approximately 10 ml of 0.9% sodium chloride solution should be added to the vial. Under exceptional circumstances, when 0.9% sodium chloride solution cannot be used for clinical reasons, 5% glucose may be used as a solvent.

Shake well and transfer the resulting suspension into 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. The 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 interval between the start of reconstitution and the end of intravenous infusion should not exceed 2 hours.

Children.

Due to insufficient clinical data, the use of Cilpen is not recommended in children under 1 year of age and in children with impaired renal function (serum creatinine >2 mg/dL) (see subsection "Central nervous system").

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 efficacy of this procedure in overdose has not been established. Treatment is symptomatic.

Adverse Reactions

It is known that in clinical trials involving 1723 patients receiving intravenous imipenem/cilastatin, the most commonly reported systemic adverse reactions possibly related to treatment 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%), and somnolence (0.2%). The most frequently reported local adverse reactions were: phlebitis/thrombophlebitis (3.1%), pain at injection site (0.7%), erythema at injection site (0.4%), and venous induration (0.2%).

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

Adverse reactions are listed 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 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 disturbances; very rare – worsening of severe myasthenia gravis, 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 – tooth and/or tongue discoloration; 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, Quincke's edema, Stevens-Johnson syndrome, erythema multiforme, 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 (benign, should not be confused with hematuria). The effect of the drug on renal function changes 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.

It is known that in studies involving 178 children older than 3 months, adverse reactions were entirely similar to those observed in adult patients.

Reporting of adverse reactions after drug registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of drug efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Incompatibilities. The medicinal product is chemically incompatible with lactates (salts of lactic acid) and must not be diluted with solvents containing lactates. However, Cilpen may be administered through the same intravenous system used for lactate solution infusion.

The product must not be mixed with other antibiotics or any other medicinal products except those specified in the section "Administration and dosage."

Packaging. 1 g of powder in vials made of colorless glass. Packs of 1, 10, or 50 vials.

Prescription category. Prescription only.

Manufacturer. Private Joint-Stock Company "Lekhym-Kharkiv".

Manufacturer's address and location of business activity.
36 Severina Pototskoho Street, Kharkiv, Kharkiv Oblast, 61115, Ukraine.