Imifors

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

Composition:

Active substances: imipenem and cilastatin;

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

Excipient: sodium hydrogencarbonate.

Pharmaceutical form. Powder for solution for infusion.

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

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

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

The medicinal product Imiforce consists of two components: imipenem and cilastatin sodium in a 1:1 weight ratio.

Imipenem, alternatively 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 bacterial cell wall synthesis in Gram-positive and Gram-negative bacteria through binding to penicillin-binding proteins (PBPs).

Cilastatin sodium is an inhibitor that exerts a competitive, reversible, and specific action on dehydropeptidase-I, a renal enzyme that metabolizes and inactivates imipenem. It has no intrinsic antibacterial activity and does not affect the antibacterial activity of imipenem.

Pharmacokinetic/pharmacodynamic (PK/PD) relationship

As with other beta-lactam antibiotics, the parameter that best correlates with efficacy is the duration of time during which the concentration of imipenem 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);
• imipenem may be actively expelled from the cell via efflux pumps;
• reduced affinity of imipenem for penicillin-binding proteins (PBPs);
• imipenem is stable against hydrolysis by most beta-lactamases, including penicillinases and cephalosporinases produced by Gram-positive and Gram-negative bacteria, except for relatively rare beta-lactamases capable of hydrolyzing carbapenems. Organisms resistant to other carbapenems generally display co-resistance to imipenem. There is no cross-resistance at the target site between imipenem and quinolone antibiotics, aminoglycosides, macrolides, or tetracyclines.

Breakpoints

The European Committee on Antimicrobial Susceptibility Testing (EUCAST) has established the following MIC breakpoints for imipenem (v.12.0, 01.01.2022):

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 identification and antimicrobial susceptibility testing of any isolate should be confirmed, and the isolate should be sent to a reference laboratory.

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

Susceptibility

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

Usually susceptible species:

Gram-positive aerobic bacteria

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 bacteria

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 bacteria

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

Gram-negative anaerobic bacteria

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 bacteria

Acinetobacter calcoaceticus baumannii complex, Pseudomonas aeruginosa.

Naturally resistant species:

Gram-positive aerobic bacteria

Enterococcus faecium.

Gram-negative aerobic bacteria

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

Others:

Chlamydia spp., Chlamydophila spp., Mycoplasma spp., Ureaplasma urealyticum.

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

** Non–strain-associated breakpoints according to EUCAST are used.

Pharmacokinetics.

Imipenem

Absorption

In healthy volunteers, intravenous infusion of imipenem/cilastatin at a dose of 500 mg/500 mg over 20 minutes resulted in plasma concentrations of imipenem ranging from 12 to 20 mcg/mL for the 250 mg/250 mg dose, from 21 to 58 mcg/mL for the 500 mg/500 mg dose, and from 41 to 83 mcg/mL for the 1000 mg/1000 mg dose. The mean peak plasma concentration of imipenem after administration of 250 mg/250 mg, 500 mg/500 mg, and 1000 mg/1000 mg doses was 17, 39, and 66 mcg/mL, respectively. Plasma concentrations of imipenem declined to less than 1 mcg/mL within 4–6 hours.

Distribution

Plasma protein binding of imipenem is approximately 20%.

Metabolism

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

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

Elimination

The elimination half-life of imipenem in plasma is approximately 1 hour. Approximately 70% of the administered antibiotic was recovered unchanged in urine within 10 hours, with no further urinary excretion of imipenem observed. Imipenem concentrations in urine exceeded 10 mcg/mL for up to 8 hours after administration of a 500 mg/500 mg dose of imipenem/cilastatin. The remainder of the administered dose was excreted in urine as antibacterially inactive metabolites, and fecal elimination of imipenem was virtually negligible.

When Imifors was administered every 6 hours, no accumulation of imipenem in plasma or urine was observed in patients with normal renal function.

Cilastatin

Absorption

The peak plasma concentration of cilastatin after a 20-minute intravenous infusion of imipenem/cilastatin was 21–26 mcg/mL for the 250 mg/250 mg dose, 21–55 mcg/mL for the 500 mg/500 mg dose, and 56–88 mcg/mL for the 1000 mg/1000 mg dose. The mean peak plasma concentration of cilastatin after administration of 250 mg/250 mg, 500 mg/500 mg, and 1000 mg/1000 mg doses was 22, 42, and 72 mcg/mL, respectively.

Distribution

Plasma protein binding of cilastatin 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 of imipenem/cilastatin. After this period, cilastatin was no longer detected in urine. Approximately 10% was excreted as the N-acetyl metabolite, which has inhibitory activity against dehydropeptidase-I comparable to that of cilastatin. Renal dehydropeptidase-I activity returned to normal shortly after elimination of cilastatin from the bloodstream.

Pharmacokinetics in special patient populations

Renal impairment

After a single intravenous dose of imipenem/cilastatin 250 mg/250 mg, the area under the concentration-time curve (AUC) for imipenem increased by 1.1, 1.9, and 2.7 times, respectively, in patients with mild (creatinine clearance (CrCL) 50–80 mL/min/1.73 m²), moderate (CrCL 30 to <50 mL/min/1.73 m²), and severe (CrCL <30 mL/min/1.73 m²) renal impairment 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 intravenous dose of imipenem/cilastatin 250 mg/250 mg 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. Following intravenous administration of Imifors, urinary excretion, renal clearance, and plasma clearance of imipenem and cilastatin decrease with declining renal function. 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 has 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 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 in adults receiving a 500 mg/500 mg dose. At a higher dose, exposure after administration of 25/25 mg/kg imipenem/cilastatin to 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 expected values in patients with mild renal impairment, for whom no dose adjustments are considered necessary. Mean elimination half-lives of imipenem and cilastatin in plasma were 91 ± 7 minutes and 69 ± 15 minutes, respectively. Multiple dosing did not affect the pharmacokinetics of imipenem or cilastatin, and no accumulation of imipenem/cilastatin was observed (see section "Dosage and administration").

Clinical characteristics.

Indications.

The medicinal product Imifors is indicated for the treatment of the following infections in adults and children aged 1 year and older:

• complicated intra-abdominal infections;
• severe pneumonia, including hospital-acquired and ventilator-associated pneumonia;
• intrapartum and postpartum infections;
• complicated urinary tract infections;
• complicated skin and soft tissue infections.

Imifors may be used in the treatment of patients with febrile neutropenia, where bacterial infection is the suspected cause.

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

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

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

Generalized seizures have been reported in patients receiving intravenous Imifors concomitantly with ganciclovir. These drugs may be used together only if the expected benefit outweighs the potential risk.

Reduced plasma levels of valproic acid to values potentially below the therapeutic range have been reported when valproic acid is co-administered with carbapenems. Decreased valproic acid levels may lead to inadequate seizure control; therefore, concomitant administration of imipenem and valproic acid/sodium valproate is not recommended. Consideration should also be given to using alternative antibacterial or anticonvulsant therapy (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 patient status, 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 Imifors and probenecid resulted in minimal increases in plasma concentrations and elimination half-life of imipenem. Renal excretion of active (unmetabolized) imipenem decreased to approximately 60% of the dose when Imifors was administered with probenecid. Concomitant use of Imifors and probenecid doubled the plasma levels and elimination half-life of cilastatin, but had no effect on cilastatin excretion in urine.

Children

Interaction studies have been conducted only in adults.

Special precautions for use.

General recommendations

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

Hypersensitivity reactions

Severe, and sometimes fatal, hypersensitivity reactions (including anaphylaxis) have been reported in patients receiving β-lactam antibiotics. Such reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens. Prior to initiating therapy with this drug, the patient's medical history should be carefully reviewed for 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. Severe 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).

Use in patients with liver disease: patients with pre-existing liver disease require monitoring of liver function during treatment with imipenem/cilastatin. Dose adjustment is not required (see section "Dosage and administration").

Hematological investigations

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

Antibacterial spectrum

Prior to any empirical therapy, the antibacterial spectrum of imipenem/cilastatin should be considered, especially in conditions that are life-threatening. 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. Use of imipenem/cilastatin is appropriate for treatment of 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 medicinal product 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").

Clostridioides difficile

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

Meningitis

The medicinal product Imifors is not recommended for the treatment of meningitis.

Renal function impairment

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 (see section "Dosage and administration" and subsection "Central nervous system" below).

Central nervous system

Adverse reactions affecting the CNS, such as myoclonia, confusion, or seizures, have been reported, particularly when recommended doses based on renal function and body weight have been exceeded. Such disorders usually occurred in patients with 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 doses and treatment regimens is essential, especially for such patients (see section "Dosage and administration"). Anticonvulsant therapy should be continued in patients with a history of seizures.

Particular caution is required in children with known risk factors for seizures and in children receiving concomitant treatment with medications that reduce seizure threshold.

If focal tremor, myoclonia, 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 Imifors should be reduced or the drug discontinued.

The medicinal product Imifors is not indicated for use in patients with creatinine clearance < 15 ml/min, except when hemodialysis will be performed within 48 hours. For patients undergoing hemodialysis, Imifors is recommended only when the expected therapeutic benefit outweighs the potential risk of seizures (see section "Dosage and administration").

Sodium

This medicinal product contains 37.6 mg (1.6 mmol)/dose of sodium. Caution should be exercised when administering this product to patients on a sodium-restricted 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 in pregnant monkeys. The potential risk to humans is unknown. Imifors may be used during pregnancy only if the expected benefit to the pregnant woman outweighs the potential risk to the fetus.

Breastfeeding period.

Imipenem and cilastatin are excreted in small amounts in 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 on the potential effect of imipenem/cilastatin treatment on male or female fertility.

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 reactions (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").

Administration and Dosage

Dosage

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

The daily dose of Imifos should be determined based on the type of infection and divided into several equal doses, taking into account the pathogen's sensitivity level 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 treatment of infections likely or confirmed to be caused by less susceptible bacterial species (such as Pseudomonas aeruginosa) and for severe infections (e.g., febrile neutropenia), a dosage of 1000 mg/1000 mg every 6 hours is recommended.

Dosage adjustment is required when creatinine clearance is < 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 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) according to the patient's creatinine clearance. Information regarding infusion duration is provided below in the section "Administration and Dosage".

Patients with creatinine clearance < 15 ml/min

The medicinal product Imifors should not be administered to patients with creatinine clearance < 15 ml/min unless they are scheduled for hemodialysis within the next 48 hours.

Patients undergoing hemodialysis

For treatment of patients with creatinine clearance < 15 ml/min who are on 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. The medicinal product Imifors should be administered to the patient immediately after the hemodialysis session and then every 12 hours following its completion. Patients undergoing hemodialysis, especially those with underlying central nervous system (CNS) disorders, require close monitoring; administration of Imifors to such patients is recommended only if the expected benefit outweighs the potential risk of seizures (see section "Special precautions").

There is currently insufficient data on the use of Imifors in patients undergoing peritoneal dialysis; therefore, its use in this patient group is not recommended.

Hepatic impairment

Dosage adjustment is not required for patients with hepatic impairment.

Elderly patients

Dosage adjustment is not required for 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 every 6 hours.

For treatment of infections where less susceptible organisms (such as Pseudomonas aeruginosa) are established or likely causative agents, and for very 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 renal impairment (serum creatinine > 2 mg/dL) due to insufficient clinical data.

Administration method

Prior to administration, the medicinal product Imifors must be reconstituted and then diluted.

A dose of Imifors for intravenous administration not exceeding 500 mg/500 mg should be infused over 20–30 minutes. A dose exceeding 500 mg/500 mg should be infused 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 contents of each vial should be transferred into 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 solvent.

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

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

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

Repeat the procedure by adding another 10 ml of the 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 the medicinal product Imifors is not recommended in children under 1 year of age and in children with renal impairment (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 treatment of overdose with this drug. The drug can be removed by hemodialysis; however, the effectiveness of this procedure in overdose has not been established. Treatment is symptomatic.

Side effects

In clinical trials involving 1723 patients who received intravenous imipenem/cilastatin, the most commonly reported systemic adverse reactions possibly related to treatment were: nausea (2.0%), diarrhea (1.8%), vomiting (1.5%), rash (0.9%), fever (0.5%), arterial hypotension (0.4%), seizures (0.4%) (see section "Special precautions"), dizziness (0.3%), pruritus (0.3%), urticaria (0.2%), and 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%). Elevations in serum transaminases and alkaline phosphatase levels were also observed.

The adverse reactions and their frequencies listed below were identified based on clinical trial results and post-marketing experience. Adverse reactions 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).

Within each frequency group, adverse reactions are listed in order of decreasing severity.

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, pharyngalgia.

Gastrointestinal disorders: common – diarrhea, vomiting, nausea (nausea and/or vomiting associated with the medicinal product 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 – hepatic 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, 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 role of the drug in 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, injection site erythema; very rare – chest discomfort, asthenia/weakness.

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

Children aged > 3 months

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued 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 efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

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

Do not freeze reconstituted solutions.

The shelf life of reconstituted solutions is specified in the section "Dosage and administration".

Incompatibilities.

The medicinal product is chemically incompatible with lactates (salts of lactic acid) and therefore should not be diluted with solvents containing lactates. However, the product may be administered through the same intravenous line used for lactate-containing infusions.

The medicinal product Imifors for intravenous use must not be mixed with other medicinal products except those specified in the subsection "Reconstitution".

Packaging.

Powder in a glass vial closed with a rubber stopper and an aluminum cap with a "flip-off" component, 1 vial per carton.

Prescription status. Prescription only.

Manufacturer. Venus Remedies Limited.

Manufacturer's address and place of business.

Hill Top Industrial Estate, Jharmajri ERIPR Phase 1 Extension Batoli Kalan, Solan, Baddi, 173205, India.

Marketing authorization holder. Ananta Medicare Ltd.

Address of the marketing authorization holder and/or its representative.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.