INSTRUCTION

for medical use of the medicinal product

 

IMIFORS

Composition:

active substance: imipenem and cilastatin;

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

excipients: sodium bicarbonate.

 

Dosage form. Powder for solution for infusion.

Basic physical and chemical properties: white to light yellow powder.

 

Pharmacotherapeutic group.

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

 

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

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

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

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

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

Pharmacokinetic/pharmacodynamic relationship (PK/PD)

As with other beta-lactam antibiotics, the time during which imipenem concentrations exceed the minimum inhibitory concentration (T > MIC) is the parameter that best correlates with efficacy.

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 an efflux pump;
• - decreased affinity of imipenem for penicillin-binding proteins;
• - imipenem is resistant to hydrolysis by most beta-lactamases, including penicillinases and cephalosporinases produced by Gram-positive and Gram-negative bacteria, with the exception of relatively rare beta-lactamases capable of hydrolysing carbapenems. Species resistant to other carbapenems generally exhibit cross-resistance to imipenem. There is no target-level cross-resistance between imipenem and fluoroquinolones, aminoglycosides, macrolides, or tetracyclines.

Breakpoints

The following MIC breakpoints for imipenem have been established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) (v.12.0 dated 01.01.2022):

 

Microorganism group	Minimum Inhibitory Concentration (mg/L)
	Susceptible ≤	Resistant >
Enterobacterales	2	4
Enterobacterales1 (Morganella morganii, Proteus spp. та Providencia spp.) Pseudomonas spp.	0.001   0.001	4      4
Acinetobacter spp.	2	4
Staphylococcus spp.	Based on cefoxitin susceptibility data
Enterococcus spp.	0.001	4
Streptococcus A, B, C, G	Based on benzylpenicillin susceptibility data
Streptococcus pneumoniae	2	2
Viridans group streptococci	2	2
Haemophilus influenzae	2	2
Moraxalla catarrhalis2	2	2
Gram-positive anaerobic microorganisms, excluding Clostridioides difficile	2	4
Gram-negative anaerobic microorganisms	2	4
Burkholderia pseudomallei	2	2
Non-species-related breakpoints3	2	4

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

² Resistant isolates are rare or have not yet been reported. Identification and antimicrobial susceptibility test results for any such isolate should be verified, and the isolate should be sent to a reference laboratory.

³ Non-species-related breakpoints were determined primarily based on pharmacokinetic/pharmacodynamic (PK/PD) data and independently of the MIC distribution for specific species. These breakpoints are intended for use only with species not mentioned in the species-related breakpoint overview or in the notes.

 

Susceptibility

The prevalence of acquired resistance may vary geographically and over time for selected species, and local information on resistance is desirable, particularly when treating severe infections. When necessary, expert advice should be sought if the local prevalence of resistance is such that the utility of the medicinal product in at least some types of infections is questionable.

Commonly susceptible species:

Gram-positive aerobic bacteria

Enterococcus faecalis, Staphylococcus aureus (methicillin-susceptible)*, coagulase-negative Staphylococcus (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 a concern:

Gram-negative aerobic bacteria

Acinetobacter calcoaceticus baumannii complex, Pseudomonas aeruginosa.

Inherently 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-species-related EUCAST breakpoints are applied.

 

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 imipenem levels ranging from 12 to 20 µg/mL for the 250 mg/250 mg dose, 21 to 58 µg/mL for the 500 mg/500 mg dose, and 41 to 83 µg/mL for the 1000 mg/1000 mg dose. The mean peak plasma concentrations of imipenem following administration of 250 mg/250 mg, 500 mg/500 mg, and 1000 mg/1000 mg were 17, 39, and 66 µg/mL, respectively. Plasma concentrations of imipenem decreased to below 1 µg/mL within 4 to 6 hours after administration.

Distribution

The plasma protein binding of imipenem in humans is approximately 20%.

Metabolism

When administered alone, imipenem is metabolized in the kidneys by dehydropeptidase-I. Individual urinary recovery ranged from 5% to 40%, with an average of 15–20% across several studies.

Cilastatin is a specific inhibitor of the dehydropeptidase-I enzyme and effectively prevents the metabolism of imipenem. As such, the co-administration of imipenem and cilastatin allows for therapeutic antibacterial concentrations of imipenem to be achieved in both urine and plasma.

Elimination

The plasma half-life of imipenem is approximately 1 hour. About 70% of the administered dose is recovered unchanged in urine within 10 hours; no further urinary elimination of imipenem is observed thereafter. Urinary concentrations of imipenem exceed 10 µg/mL for up to 8 hours following administration of a 500 mg/500 mg dose. The remaining dose is excreted in the urine as microbiologically inactive metabolites, and faecal excretion of imipenem is negligible.

No accumulation of imipenem in plasma or urine was observed during treatment with Imifors administered every 6 hours in patients with normal renal function.

Cilastatin

Absorption

The peak plasma concentrations of cilastatin after a 20-minute intravenous infusion of imipenem/cilastatin were 21 to 26 µg/mL for the 250 mg/250 mg dose, 21 to 55 µg/mL for the 500 mg/500 mg dose, and 56 to 88 µg/mL for the 1000 mg/1000 mg dose. Mean peak plasma concentrations following administration of 250 mg/250 mg, 500 mg/500 mg, and 1000 mg/1000 mg were 22, 42, and 72 µg/mL, respectively.

Distribution

The plasma protein binding of cilastatin in humans is approximately 40%.

Metabolism and elimination

The plasma half-life of cilastatin is approximately 1 hour. About 70–80% of the administered cilastatin dose is excreted unchanged in the urine within 10 hours of administration of imipenem/cilastatin; no further urinary excretion is detected thereafter. Approximately 10% of the dose is recovered as the N-acetyl metabolite, which retains dehydropeptidase-inhibitory activity comparable to that of cilastatin. Renal dehydropeptidase-I activity returns to baseline shortly after cilastatin is eliminated from the bloodstream.

Pharmacokinetics in special populations

Renal impairment

Following a single intravenous dose of imipenem/cilastatin 250 mg/250 mg, the area under the plasma concentration–time curve (AUC) for imipenem increased by approximately 1.1-, 1.9-, and 2.7-fold 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, respectively, compared with subjects with normal renal function (CrCL > 80 mL/min/1.73 m²).

For cilastatin, the AUC increased by approximately 1.6-, 2-, and 6.2-fold in patients with mild, moderate, and severe renal impairment, respectively, compared with those with normal renal function. Following a single intravenous dose of imipenem/cilastatin 250 mg/250 mg administered 24 hours after haemodialysis, the AUCs of imipenem and cilastatin were approximately 3.7- and 16.4-fold higher, respectively, compared to subjects with normal renal function. After intravenous administration of Imifors, urinary excretion, renal clearance, and plasma clearance of imipenem and cilastatin decreased with worsening renal function. Dose adjustment is required in patients with impaired renal function (see section "Method of administration and dosage").

Hepatic impairment

The pharmacokinetics of imipenem in patients with hepatic impairment has not been established. However, since imipenem undergoes minimal hepatic metabolism, hepatic impairment is not expected to affect its pharmacokinetics. Therefore, dose adjustment is not recommended for patients with hepatic impairment (see section "Method of administration and dosage").

Paediatric population

The mean 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 following administration of imipenem/cilastatin at a dose of 15/15 mg/kg in children was approximately 30% higher than that observed in adults receiving a 500 mg/500 mg dose. At a higher dose of 25/25 mg/kg in children, the exposure was approximately 9% greater than in adults who received 1000 mg/1000 mg.

Elderly

In healthy elderly volunteers (aged 65–75 years) with normal renal function for their age, the pharmacokinetics of a single 500 mg/500 mg intravenous dose of imipenem/cilastatin administered over 20 minutes were consistent with those observed in patients with mild renal impairment, for whom dose adjustment is generally not required. The mean elimination half-life values for imipenem and cilastatin were 91 ± 7 minutes and 69 ± 15 minutes, respectively. Multiple dosing had no effect on the pharmacokinetics of imipenem or cilastatin, and no accumulation of imipenem/cilastatin was observed (see section "Method of administration and dosage").

 

Clinical particulars.

Indications.

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 management of neutropenic patients with fever that is suspected to be due to a bacterial infection.

Treatment of patients with bacteraemia that is associated with, or suspected to be associated with, any of the infections listed above.

Official guidelines on the appropriate use of antibacterial agents should be considered.

 

Contraindications.

Hypersensitivity to any of the active substances or excipients, to any other carbapenem antibacterial agent, or severe hypersensitivity reactions (e.g. anaphylaxis, severe skin reactions) to any 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 should be co-administered only if the expected benefit outweighs the potential risk.

Co-administration of carbapenems with valproic acid has been reported to reduce plasma levels of valproic acid to subtherapeutic concentrations. This reduction may lead to inadequate seizure control. Therefore, concomitant use of imipenem and valproic acid/valproate sodium is not recommended. Alternative antibacterial or antiepileptic therapy should be considered (see section "Precautions for use").

Oral anticoagulants

Concomitant use of antibiotics with warfarin may enhance the anticoagulant effect of warfarin. Numerous reports have documented increased anticoagulation effects, including elevated International Normalized Ratio (INR), in patients taking oral anticoagulants with antibiotics. The risk may vary depending on the type of infection, patient age, and overall condition, making it difficult to determine the antibiotic's precise role in INR elevation. Frequent INR monitoring is recommended during and after concomitant use of antibiotics with oral anticoagulants.

Co-administration of Imifors with probenecid results in a minimal increase in plasma concentrations and half-life of imipenem. Renal excretion of active (unmetabolized) imipenem decreases to approximately 60% of the administered dose when given with probenecid. Probenecid doubles plasma concentrations and half-life of cilastatin but has no effect on its urinary excretion.

Paediatric population

Interaction studies have been conducted only in adults.

 

Precautions for use.

General recommendations

When selecting imipenem/cilastatin for treatment of an individual patient, the appropriateness of using a carbapenem antibacterial agent should be carefully considered. This includes evaluating the severity of the infection, the prevalence of resistance to other relevant antibacterial agents, and the risk of selecting imipenem/cilastatin for treatment of infections caused by carbapenem-resistant bacteria.

Hypersensitivity reactions

Severe, 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. Before initiating therapy, a detailed history of hypersensitivity reactions to carbapenems, penicillins, cephalosporins, other β-lactam antibiotics, and other allergens should be obtained (see section “Contraindications”). If an allergic reaction occurs during treatment, the medicinal product should be discontinued immediately. Serious anaphylactic reactions require immediate emergency treatment.

Hepatic function

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

Use in patients with liver disease: Patients with pre-existing liver disorders should have hepatic function monitored while receiving imipenem/cilastatin. Dose adjustment is not necessary (see section “Method of administration and dosage”).

Haematologic investigations

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

Antibacterial spectrum

Before initiating empirical treatment, the antibacterial spectrum of imipenem/cilastatin should be considered, especially in life-threatening conditions. Additionally, caution is advised due to limited susceptibility of certain 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 when the specific pathogen has been documented and is known to be susceptible, or when there are compelling reasons to believe that the likely pathogen(s) are suitable for such treatment. Co-administration of an agent active against methicillin-resistant Staphylococcus aureus (MRSA) may be warranted when MRSA involvement is suspected or confirmed in approved indications. Co-administration of an aminoglycoside may be warranted when Pseudomonas aeruginosa infection is suspected or confirmed in approved indications (see section “Indications”).

Interaction with valproic acid

Concomitant use of imipenem/cilastatin with 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 have been reported with imipenem/cilastatin, as with nearly all antibiotics. These conditions may range in severity from mild to life-threatening. This diagnosis should be considered in patients who develop diarrhea during or after treatment with imipenem/cilastatin (see section “Adverse reactions”). Discontinuation of imipenem/cilastatin and initiation of specific treatment for Clostridioides difficile should be considered. Products that inhibit peristalsis should not be used.

Meningitis

Imifors is not recommended for the treatment of meningitis.

Renal impairment

Imipenem and cilastatin accumulate in patients with impaired renal function. CNS adverse reactions may occur if the dose is not adjusted based on renal function (see section “Method of administration and dosage” and subsection “Central nervous system” below).

Central nervous system

CNS adverse reactions, such as myoclonus, confusion, or seizures, have been reported, particularly when the recommended dosage was exceeded based on renal function and body weight. Such effects were typically observed in patients with underlying CNS disorders (e.g., brain lesions or a history of seizures) and/or renal impairment, where drug accumulation is possible. Therefore, it is critically important, especially in such patients, to adhere strictly to the recommended dosing and treatment schedule (see section “Method of administration and dosage”). Anticonvulsant therapy should be continued in patients with a history of seizures.

Special caution is advised in children with known seizure risk factors and those receiving concomitant anticonvulsant therapy.

If focal tremor, myoclonus, or seizures occur during treatment, a neurological evaluation should be conducted and anticonvulsant therapy initiated if not already in place. If CNS symptoms persist, the dosage of Imifors should be reduced or treatment discontinued.

Imifors is not recommended in patients with a creatinine clearance < 15 mL/min unless haemodialysis is initiated within 48 hours. In patients on haemodialysis, Imifors should only be used when the expected benefit outweighs the potential risk of seizures (see section “Method of administration and dosage”).

Sodium content

This medicinal product contains 37.6 mg (1.6 mmol) of sodium per dose. Caution should be exercised when administering the product to patients on a sodium-controlled diet.

 

Pregnancy and lactation.

Pregnancy.

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

Reproductive toxicity was observed in studies conducted on pregnant monkeys. The potential risk to humans is unknown. Imifors should be used during pregnancy only if the potential benefit to the mother justifies the possible risk to the foetus.

Breastfeeding.

Imipenem and cilastatin are excreted in small amounts in human breast milk. Therefore, it is unlikely that a breast-fed infant would be exposed to significant amounts of the drug. If use of the medicinal product is necessary, the benefit of breastfeeding for the child and the potential risk associated with the use of the medicinal product should be carefully considered.

Fertility.

There are no data on the potential effects of treatment with imipenem/cilastatin on male or female fertility.

 

Effects on ability to drive and use machines.

No studies on the effects of the medicinal product on the ability to drive and use machines have been carried out.

However, some adverse reactions (such as hallucinations, somnolence, dizziness, and vertigo) associated with the use of the medicinal product may affect the ability of certain patients to drive or operate machinery (see section “Adverse reactions”).

 

Method of administration and dosage.

Dosage

The recommended doses of Imifors refer to the amount of imipenem/cilastatin to be administered.

The total daily dose of Imifors should be determined based on the type of infection and divided into several equal doses, taking into account the susceptibility of the pathogen(s) and the patient's renal function status.

Adults and adolescents

The recommended dosing regimen for patients with normal renal function (creatinine clearance ≥ 90 mL/min) is:

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

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

The dose should be reduced if 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 a 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 used in patients with normal renal function.
2. Select the appropriate reduced dosing regimen (see table) based on the patient’s creatinine clearance. For information regarding infusion duration, see section “Method of administration and dosage” below.

 

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

 

Patients with creatinine clearance < 15 ml/min

Imifors should not be administered to patients with a creatinine clearance < 15 mL/min unless haemodialysis is to be performed within the next 48 hours.

Patients on haemodialysis

In patients with creatinine clearance < 15 mL/min who are undergoing haemodialysis, the dosing recommendations for patients with creatinine clearance of 15–29 mL/min should be followed (see table).

Both imipenem and cilastatin are removed during haemodialysis. Imifors should be administered immediately after a haemodialysis session and then every 12 hours thereafter. Patients on haemodialysis, particularly those with underlying CNS disorders, should be closely monitored; Imifors should be prescribed to these patients only when the expected benefit outweighs the potential risk of seizures (see “Precautions for use”).

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

 

Hepatic impairment

No dose adjustment is required in patients with hepatic impairment.

Elderly

No dose adjustment is required in elderly with normal renal function.

Children over 1 year of age

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

For infections known or likely to be caused by less susceptible organisms (e.g., Pseudomonas aeruginosa) and for very severe infections (e.g., febrile neutropenia), the recommended dose is 25/25 mg/kg every 6 hours.

Children under 1 year of age

Use of Imifors is not recommended in children under 1 year of age due to insufficient clinical data.

Children with renal impairment

Use of Imifors is not recommended in children with renal impairment (serum creatinine > 2 mg/dL) due to insufficient clinical data.

Method of administration

Imifors must be reconstituted and then diluted prior to administration.

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

Reconstitution

Each vial is intended for single use only.

The contents of each vial should be transferred to 100 mL of a suitable infusion solution (0.9% sodium chloride). If 0.9% sodium chloride cannot be used for clinical reasons, 5% glucose may be used as an alternative.

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 infusion solution container.

WARNING: THE SUSPENSION IS NOT A FINAL INFUSION SOLUTION.

Repeat the procedure by adding another 10 mL of the infusion solution to the vial to ensure complete transfer of the vial contents to the infusion container. Shake the final mixture until clear.

The final concentration of the solution after this procedure is approximately 5 mg/mL of imipenem and cilastatin.

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

 

Children.

Due to insufficient clinical data, the use of Imifors is not recommended for children under 1 year of age and children with renal impairment (serum creatinine > 2 mg/dL) (see “Method of administration and dosage”).

 

Overdose.

Symptoms of overdose that may occur are consistent with the adverse reaction profile; they may include seizures, confusion, tremors, nausea, vomiting, hypotension and bradycardia. No specific information is available regarding the treatment of overdose caused by Imifors. Imifors may be removed by hemodialysis, although the efficacy of this procedure in overdose has not been established. The treatment is symptomatic.

 

Adverse reactions.

In clinical trials involving 1723 patients treated with imipenem/cilastatin intravenous, the most frequently reported systemic adverse reactions that were possibly related to therapy were as follows: nausea (2.0%), diarrhoea (1.8%), vomiting (1.5%), rash (0.9%), fever (0.5%), hypotension (0.4%), seizures (0.4%), dizziness (0.3%), pruritus (0.3%), urticaria (0.2%), somnolence (0.2%); the most frequently reported local adverse reactions were phlebitis/thrombophlebitis (3.1%), pain at the injection site (0.7%), erythema at the injection site (0.4%) and vein induration (0.2%); increases in serum transaminases and alkaline phosphatase are also commonly reported.

The following adverse reactions have been reported in clinical studies or during post-marketing experience. The adverse reactions have been categorized 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) and not known (cannot be estimated from the available data).

In each group, the frequency of adverse reactions is listed in descending order of 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 – haemolytic anaemia, bone marrow depression.

Immune system disorders: rare – anaphylactic reactions.

Psychiatric disorders: uncommon – psychic disturbances including hallucinations and confusional state.

Nervous system disorders: uncommon- seizures, myoclonic activity, dizziness, somnolence; rare – encephalopathy, paraesthesia, focal tremor, taste perversion; very rare – aggravation of myasthenia gravis, headache; not known – agitation, dyskinesia.

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

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

Vascular disorders: common – thrombophlebitis; uncommon – hypotension; very rare – hot flushes.

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

Gastrointestinal disorders: common – diarrhoea, vomiting, nausea. Medicinal product-related nausea and/or vomiting appear to occur more frequently in granulocytopenic patients than in non-granulocytopenic patients treated with the preparation. Rare – staining of teeth and/or tongue; very rare – haemorrhagic colitis, abdominal pain, heartburn, glossitis, tongue papilla hypertrophy, hypersalivation.

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, angioedema, 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, urine discoloration (harmless and should not be confused with haematuria). The role of the drug in changes in renal function is difficult to assess, as there were usually predisposing factors for prerenal azotaemia or impaired renal function.

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

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

Investigations: common – increases in serum transaminases, increases in serum alkaline phosphatase; uncommon – a positive direct Coombs' test, prolonged prothrombin time, decreased haemoglobin, increases in serum bilirubin, elevations in serum creatinine, elevations in blood urea nitrogen.

Children aged > 3 months

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

 

Adverse Reactions Reporting

Adverse reactions reporting after the registration of a medicinal product is of great importance. It enables the monitoring of the benefit/risk ratio associated with the use of the medicinal product. Healthcare professionals, pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and cases of lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

 

Shelf-life. 2 years.

Storage conditions.

Store at a temperature not exceeding 25˚C in the original manufacturer’s packaging.

Keep out of reach of children.

Do not freeze the reconstituted solutions of the medicinal product.

The shelf life of reconstituted solutions is given in the section "Method of administration and dosage".

 

Incompatibility.

The medicinal product is chemically incompatible with lactate (lactic acid salts) and shall not be reconstituted in diluters containing lactate. Nevertheless, the product may be administered through the same intravenous line as that used for the infusion of lactate-containing solutions.

Imifors for intravenous administration must not be mixed with other medicinal products except those mentioned in the “Reconstitution” subsection.

Packaging.

Powder in a glass vial closed with a rubber stopper and an aluminium cap with a flip-off component, 1 vial in a box.

 

Terms of dispensing. On prescription.

 

Date of last update.

18.10.2023