Imipenem/cilastatin - vista: detailed information

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT IMIPENEM/CILASTATIN-VISTA (IMIPENEM/CILASTATIN-VISTA)

Composition:

Active substances:

1 vial contains 530 mg of imipenem monohydrate, equivalent to 500 mg of imipenem, and 530 mg of sodium cilastatin, equivalent to 500 mg of cilastatin;

Excipient: sodium bicarbonate.

Pharmaceutical form. Powder for solution for infusion.

Main physicochemical properties: white to almost white or slightly yellowish powder.

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

Pharmacological Properties.

Pharmacodynamics.

The medicinal product Imipenem/Cilastatin-Vista consists of two components: imipenem, the first representative of a new class of β-lactam antibiotics – thienamycins, and sodium cilastatin, a specific inhibitor of the enzyme that blocks imipenem metabolism in the kidneys and significantly increases the concentration of unchanged imipenem in the urinary tract. The weight ratio of imipenem to sodium cilastatin in the medicinal product is 1:1. The class of thienamycin antibiotics, to which imipenem belongs, is characterized by a broader spectrum of potent bactericidal activity than that provided by any of the studied antibiotics.

The medicinal product Imipenem/Cilastatin-Vista is indicated for the treatment of mixed infections caused by susceptible strains of aerobic and anaerobic bacteria. This drug has demonstrated efficacy in treating many infections caused by aerobic and anaerobic gram-positive and gram-negative bacteria resistant to cephalosporins, including cefazolin, cefoperazone, cephalothin, cefoxitin, cefotaxime, moxalactam, cefamandole, ceftazidime, and ceftriaxone. A large number of infections caused by pathogens resistant to aminoglycosides (gentamicin, amikacin, tobramycin) and/or penicillins (ampicillin, carbenicillin, penicillin-G, ticarcillin, piperacillin, azlocillin, mezlocillin) are also effectively treated with this combination. The medicinal product Imipenem/Cilastatin-Vista is not indicated for the treatment of meningitis. Imipenem/Cilastatin-Vista is a potent inhibitor of bacterial cell wall synthesis and exerts bactericidal activity against a broad spectrum of gram-positive and gram-negative, aerobic and anaerobic pathogenic microorganisms.

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

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

The antibacterial spectrum of imipenem/cilastatin is broader than that of any other known antibiotic and encompasses all clinically significant pathogenic microorganisms. Microorganisms generally susceptible in vitro to the medicinal product Imipenem/Cilastatin-Vista include:

Gram-negative aerobic bacteria:

Achromobacter species

Acinetobacter species (formerly Mima-Herellea)

Aeromonas hydrophila

Alcaligenes species

Bordetella bronchicanis

Bordetella bronchiseptica

Bordetella pertussis

Brucella melitensis

Burkholderia pseudomallei (formerly Pseudomonas pseudomallei)

Burkholderia stutzeri (formerly Pseudomonas stutzeri)

Campylobacter species

Capnocytophaga species

Citrobacter species

Citrobacter koseri (formerly Citrobacter diversus)

Citrobacter freundii

Eikenella corrodens

Enterobacter species

Enterobacter aerogenes

Enterobacter agglomerans

Enterobacter cloacae

Escherichia coli

Gardnerella vaginalis

Haemophilus ducreyi

Haemophilus influenzae (including β-lactamase-producing strains)

Haemophilus parainfluenzae

Hafnia alvei

Klebsiella species

Klebsiella oxytoca

Klebsiella ozaenae

Klebsiella pneumoniae

Moraxella species

Morganella morganii (formerly Proteus morganii)

Neisseria gonorrhoeae (including penicillinase-producing strains)

Neisseria meningitidis

Pasteurella species

Pasteurella multocida

Plesiomonas shigelloides

Proteus species

Proteus mirabilis

Proteus vulgaris

Providencia species

Providencia alcalifaciens

Providencia rettgeri (formerly Proteus rettgeri)

Providencia stuartii

Pseudomonas species*

Pseudomonas fluorescens

Pseudomonas putida

Pseudomonas aeruginosa

Salmonella species

Salmonella typhi

Serratia species

Serratia proteamaculans (formerly Serratia liquefaciens)

Serratia marcescens

Shigella species

Yersinia species (formerly Pasteurella)

Yersinia enterocolitica

Yersinia pseudotuberculosis

*Stenotrophomonas maltophilia (formerly Xanthomonas maltophilia, formerly Pseudomonas maltophilia) and Burkholderia cepacia strains (formerly Pseudomonas cepacia) are generally not susceptible to the medicinal product Imipenem/Cilastatin-Vista.

Gram-positive aerobic bacteria

Bacillus species

Enterococcus faecalis

Erysipelothrix rhusiopathiae

Listeria monocytogenes

Nocardia species

Pediococcus species

Staphylococcus aureus (including penicillinase-producing strains)

Staphylococcus epidermidis (including penicillinase-producing strains)

Staphylococcus saprophyticus

Streptococcus agalactiae

Streptococcus group C

Streptococcus group G

Streptococcus pneumoniae

Streptococcus pyogenes

Viridans Streptococci (including α- and γ-hemolytic strains)

Enterococcus faecium and certain methicillin-resistant staphylococci are not susceptible to the medicinal product Imipenem/Cilastatin-Vista.

Gram-negative anaerobic bacteria:

Bacteroides species

Bacteroides distasonis

Bacteroides fragilis

Bacteroides ovalus

Bacteroides thetaiotaomicron

Bacteroides uniformis

Bacteroides vulgatus

Bilophila wadsworthia

Fusobacterium species

Fusobacterium necrophorum

Fusobacterium nucleatum

Porphyromonas asaccharolytica (formerly Bacteroides asaccharolyticus)

Prevotella bivia (formerly Bacteroides bivius)

Prevotella disiens (formerly Bacteroides disiens)

Prevotella intermedia (formerly Bacteroides intermedius)

Prevotella melaninogenica (formerly Bacteroides melaninogenicus)

Veillonella spp.

Gram-positive anaerobic bacteria:

Actinomyces species

Bifidobacterium species

Clostridium species

Clostridium perfringens

Eubacterium species

Lactobacillus species

Mobiluncus species

Microaerophilic streptococcus

Peptococcus species

Peptostreptococcus species

Propionibacterium species (including P. acnes)

Others

Mycobacterium fortuitum

Mycobacterium smegmatis

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

Pharmacokinetics.

Imipenem.

Absorption.

In healthy volunteers, intravenous infusion of the medicinal product over 20 minutes resulted in peak plasma concentrations of imipenem ranging from 12 µg/mL to 20 µg/mL for the 250 mg/250 mg dose, from 21 µg/mL to 58 µg/mL for the 500 mg/500 mg dose, and from 41 µg/mL to 83 µg/mL for the 1000 mg/1000 mg dose. Mean peak plasma concentrations of imipenem after administration of 250 mg/250 mg, 500 mg/500 mg, and 1000 mg/1000 mg doses were 17 µg/mL, 39 µg/mL, and 66 µg/mL, respectively. At these doses, plasma concentrations of imipenem declined to less than 1 µg/mL within 4–6 hours.

Distribution.

Imipenem binding to human serum proteins is approximately 20%. Biotransformation.

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

Cilastatin – a specific inhibitor of the enzyme dehydropeptidase-I – 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 from plasma is approximately 1 hour. Approximately 70% of the administered antibiotic is excreted unchanged in urine within 10 hours, with no further urinary excretion observed. When the medicinal product Imipenem/Cilastatin-Vista is administered every 6 hours, no accumulation of imipenem in plasma or urine was observed in patients with normal renal function. Concomitant administration of Imipenem/Cilastatin-Vista and probenecid resulted in minimal increases in plasma concentration and elimination half-life of imipenem.

Cilastatin

Absorption.

Peak plasma concentrations of cilastatin after a 20-minute intravenous infusion of the medicinal product ranged from 21 µg/mL to 26 µg/mL for the 250 mg/250 mg dose, from 21 µg/mL to 55 µg/mL for the 500 mg/500 mg dose, and from 56 µg/mL to 88 µg/mL for the 1000 mg/1000 mg dose. Mean peak plasma concentrations of cilastatin after 250 mg/250 mg, 500 mg/500 mg, and 1000 mg/1000 mg doses were 22 µg/mL, 42 µg/mL, and 72 µg/mL, respectively.

Distribution.

Cilastatin binding to human serum proteins is approximately 40%. Biotransformation and elimination.

The elimination half-life of cilastatin from plasma is approximately 1 hour. Approximately 70–80% of the administered dose of cilastatin is excreted unchanged in urine within 10 hours after administration of the medicinal product. After this, cilastatin was not detected in urine. Approximately 10% was recovered as the metabolite N-acetyl-cilastatin, which has inhibitory activity against dehydropeptidase comparable to that of the parent compound. Concomitant administration of the medicinal product and probenecid resulted in a doubling of plasma concentration and elimination half-life of cilastatin, but did not affect urinary recovery of cilastatin.

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-fold, 1.9-fold, and 2.7-fold 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). AUC for cilastatin increased by 1.6-fold, 2-fold, and 6.2-fold, 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, AUC for imipenem and cilastatin was 3.7-fold and 16.4-fold higher, respectively, compared to patients with normal renal function. Renal excretion, renal clearance, and plasma clearance of imipenem and cilastatin decrease with declining renal function following intravenous administration of Imipenem/Cilastatin-Vista. Dose adjustment is necessary for patients with impaired renal function.

Hepatic impairment.

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

Children.

Mean clearance and volume of distribution for imipenem were approximately 45% higher in children (aged 3 months to 14 years) compared to adults. AUC for imipenem after administration of imipenem/cilastatin at 15/15 mg/kg body weight 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 expected results in patients with mild renal impairment, for whom any dose adjustments are considered unnecessary. Mean elimination half-lives of imipenem and cilastatin from plasma were 91±7 minutes and 69±15 minutes, respectively. Repeated dosing did not affect the pharmacokinetics of imipenem or cilastatin, and no accumulation of imipenem/cilastatin was observed.

Clinical characteristics.

Indications.

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

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 medicinal product may be used in the treatment of patients with febrile neutropenia, likely due to bacterial infection.

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

Contraindications.

Hypersensitivity to any component of the 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 forms of interaction.

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

Reduced plasma levels of valproic acid have been reported when co-administered with carbapenems, and sudden seizures have been reported in some cases. Therefore, concomitant use of imipenem and valproic acid/sodium valproate is not recommended. Alternative antibacterial or anticonvulsant therapy should also be considered (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 condition, 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 concentrations and elimination half-life of imipenem. Renal excretion of active (unmetabolized) imipenem decreased to approximately 60% of the dose when the drug was administered with probenecid. Concomitant use of the medicinal product 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 as a treatment agent in each individual case, consideration should be given to the appropriateness of using carbapenems based on the severity of infection, prevalence of resistance to other suitable antibacterial agents, and the possibility of the presence of carbapenem-resistant bacteria.

Hypersensitivity.

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

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.

Before any empirical therapy, the antibacterial spectrum of imipenem/cilastatin should be taken into account, especially in conditions that are life-threatening to the patient. In addition, caution should be exercised due to limited susceptibility of certain pathogens (e.g., those associated with skin and soft tissue bacterial 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 very strong reasons to believe that the most likely pathogen(s) are susceptible to this treatment. Concomitant use of this medicinal product against methicillin-resistant Staphylococcus aureus (MRSA) may be indicated when MRSA infection is suspected or confirmed in approved indications. Concomitant use of an aminoglycoside may be indicated when Pseudomonas aeruginosa infection is suspected or confirmed in approved indications. Concomitant administration of imipenem/cilastatin and valproic acid/sodium valproate is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Clostridium difficile.

Pseudomembranous colitis has been reported as a complication of nearly all antibiotics, with clinical presentations ranging from mild to life-threatening. Therefore, antibiotics should be used cautiously in patients with a history of gastrointestinal disorders, particularly colitis. It is important to consider the possibility of pseudomembranous colitis in patients who develop diarrhea during or after antibiotic therapy. Discontinuation of imipenem/cilastatin therapy and initiation of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be prescribed.

Meningitis.

The medicinal product Imipenem/Cilastatin-Vista is not recommended for the treatment of meningitis.

Renal impairment.

In patients with impaired renal function, imipenem/cilastatin accumulates. If the dose is not reduced according to renal function, adverse reactions affecting the central nervous system (CNS) may occur (see section "Dosage and administration" and information below).

CNS.

As with other β-lactam antibiotics, adverse reactions affecting the CNS such as myoclonia, confusion, or seizures have been reported during treatment with Imipenem/Cilastatin-Vista, particularly when recommended doses are exceeded based on renal function and body weight. Such events have usually been observed in patients with pre-existing CNS disorders (e.g., head trauma 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 in such patients. Anticonvulsant therapy should be continued in patients with a history of seizures.

Particular attention should be paid to neurological symptoms or seizures in children with known risk factors for seizures or who are 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 Imipenem/Cilastatin-Vista should be reduced or the drug discontinued.

Imipenem/Cilastatin-Vista 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, Imipenem/Cilastatin-Vista may be used only if the expected therapeutic benefit outweighs the potential risk of seizures.

Children.

There are insufficient clinical data to recommend the use of this medicinal product in children under 1 year of age or in children with impaired renal function (serum creatinine > 2 mg/dL). See also section “CNS” above.

Important information on excipients.

The medicinal product contains 37.6 mg of sodium (1.6 mEq), which should be considered when administering it to patients on a sodium-restricted (salt-free) 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 on pregnant monkeys. The potential risk to humans is unknown. Imipenem/Cilastatin-Vista 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. When considering the use of Imipenem/Cilastatin-Vista, the benefit of breastfeeding for the infant should be weighed against the potential risk associated with the medicinal product for the infant.

Fertility.

There are no data on the potential effects of imipenem/cilastatin treatment on fertility in men or women.

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 such as hallucinations, somnolence, dizziness, and vertigo associated with the use of the medicinal product may impair a patient's ability to drive or operate machinery.

Administration and Dosage

Dosage recommendations for the medicinal product Imipenem/Cilastatin-Vista refer to the amount of imipenem/cilastatin to be administered.

The daily dose of Imipenem/Cilastatin-Vista should be determined based on the severity of infection, the type of isolated pathogen(s), and adjusted according to renal function and body weight. The total daily dose should be divided into several equal doses administered at regular intervals.

Adults and adolescents.

Dosage 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 adjustment is required for patients with creatinine clearance < 90 mL/min (see Table 1). The maximum daily dose should not exceed 4000 mg/4000 mg per day.

Adult patients with impaired renal function

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

Determine the total daily dose (i.e., 2000/2000 mg, 3000/3000 mg, or 4000/4000 mg) normally administered to patients with normal renal function.
Select the appropriate reduced dosing regimen (see Table 1) based on the patient's creatinine clearance and the duration of infusion (see 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 mg every 6 hours	1000 mg every 8 hours	1000 mg every 6 hours
reduced dose (mg) for patients with impaired renal function
< 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.

The medicinal product Imipenem/Cilastatin-Vista for intravenous administration should not be administered to patients if hemodialysis will not be performed within the next 48 hours.

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 patient should receive imipenem/cilastatin immediately after the hemodialysis session, followed by subsequent doses every 12 hours after completion of dialysis. Patients undergoing hemodialysis, especially those with underlying central nervous system (CNS) disorders, require close monitoring; imipenem/cilastatin should be administered to such patients only if the expected benefit outweighs the potential risk of seizures (see section "Special precautions").

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

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.

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

For treatment of infections caused by less susceptible bacterial species (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 and children with renal impairment.

The medicinal product is not recommended for use in children under 1 year of age and in children with renal impairment (serum creatinine >2 mg/dL) due to insufficient clinical data.

Method of administration.

Each vial is intended for single use only.

Before administration, the vial contents (powder) must be reconstituted and diluted appropriately (see recommendations below). Each dose of Imipenem/Cilastatin-Vista for intravenous administration 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.

Preparation of solution for intravenous administration.

The medicinal product Imipenem/Cilastatin-Vista for intravenous infusion is supplied as a sterile powder in vials containing 500 mg of imipenem equivalent and 500 mg of cilastatin equivalent.

Sodium hydrogencarbonate is included in Imipenem/Cilastatin-Vista as a buffer to ensure a solution pH between 6.5 and 8.5. These pH changes are not clinically significant if the solution is prepared and stored according to the instructions provided. The medicinal product contains 37.5 mg of sodium (1.6 mEq).

The sterile powder of Imipenem/Cilastatin-Vista should be reconstituted as specified in Table 2. The resulting solution should be shaken until a clear liquid is obtained. Variation in solution color from colorless to yellow does not affect the medicinal product's activity.

Table 2

Preparation of Imipenem/Cilastatin-Vista solution for intravenous administration

Dosage of the medicinal product Imipenem/Cilastatin-Vista (imipenem/cilastatin)	Required volume of solvent (ml)	Approximate average concentration of imipenem/cilastatin (mg/ml)
500/500	100	5/5

The contents of the vial should be suspended and diluted to 100 mL with the appropriate infusion solution.

At the first stage, add approximately 10 mL of 0.9% sodium chloride solution to the vial. Under exceptional circumstances, when 0.9% sodium chloride solution cannot be used for clinical reasons, 5% glucose may be used as the solvent. Shake well and transfer the resulting suspension to an infusion container.

Warning: the suspension is not a ready-to-use infusion solution.

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

Do not freeze the reconstituted solution.

Unused materials and any remaining product should be disposed of in accordance with current regulations.

Children.

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

Overdose.

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

Treatment. There is no specific information on the treatment of overdose with Imipenem/Cilastatin-Vista. The drug can be removed by hemodialysis. However, the effectiveness of this procedure in overdose has not been established. Treatment is symptomatic.

Adverse reactions

The most common systemic adverse reactions that may have been related to imipenem/cilastatin 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%), somnolence (0.2%). The most common 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 presented in Table 3 by system organ classes 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), frequency not known (cannot be estimated from available data).

Table 3

System organ class	Frequency	Adverse reactions
Infections and infestations	rare	pseudomembranous colitis, candidiasis
Infections and infestations	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, paraesthesia, focal tremor, taste disturbance
	very rare	worsening of severe myasthenia gravis, headache
	frequency not known	agitation, dyskinesia
Ear and labyrinth disorders	rare	hearing loss
Ear and labyrinth disorders	very rare	vertigo, tinnitus
Cardiac disorders	very rare	cyanosis, tachycardia, palpitations, flushing
	common	thrombophlebitis
	uncommon	arterial hypotension
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 patients without granulocytopenia)
	rare	change in tooth and/or tongue color
	very rare	haemorrhagic colitis, abdominal pain, epigastric pain, glossitis, lingual papillae hypertrophy, increased salivation
Hepatobiliary disorders	rare	hepatic failure, hepatitis
Hepatobiliary disorders	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, polymorphic erythema, exfoliative dermatitis
	very rare	hyperhidrosis, changes in skin structure
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 medicinal product in renal function changes is difficult to assess, as predisposing factors for prerenal azotemia or renal dysfunction 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
General disorders and administration site conditions	very rare	chest discomfort, asthenia/weakness
Investigations	common	increased serum transaminases, increased serum alkaline phosphatase
Investigations	uncommon	positive direct Coombs test, prolonged prothrombin time, decreased hemoglobin, increased serum bilirubin, increased serum creatinine, increased blood urea nitrogen

In children aged > 3 months, adverse reactions have been reported with imipenem/cilastatin use, entirely similar to those observed in adult patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system.

Shelf life.

3 years.

After reconstitution:

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

Storage conditions.

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

Incompatibilities.

The medicinal product is chemically incompatible with lactates (salts of lactic acid); therefore, it must not be reconstituted with solvents containing lactates. Nevertheless, Imipenem/Cilastatin-Vista may be administered via the same intravenous system used for lactate solution infusions. The medicinal product must not be mixed with other antibiotics or any other medicinal products, except those specified in the section "Directions for use".

Packaging.

1 g of powder in vials made of clear glass. 1 or 10 vials per cardboard box.

Prescription category. Prescription only.

Manufacturer. ACS DOBFAR S.P.A./ACS DOBFAR S.P.A.

Manufacturer's address and location of operations.

Nucleo Industriale S. Atto (loc. S. Nicolo' A Tordino), 64100, Teramo (TE), Italy.

Nucleo Industriale S.Atto (loc. S. Nicolo' A Tordino), 64100 Teramo (TE), Italy.