Aquapenem (Powder) Instructions for Use

Marketing Authorization Holder

Geneffic, LLC (Russia)

Manufactured By

Pharmasintez, JSC (Russia)

ATC Code

J01DH51 (Imipenem and cilastatin)

Active Substances

Imipenem (Rec.INN registered by WHO)

Cilastatin (Rec.INN registered by WHO)

Dosage Form

Aquapenem

Powder for solution for infusion 500 mg+500 mg: vial 1 pc.

Dosage Form, Packaging, and Composition

Powder for preparation of solution for infusion from white to light yellow.

Excipients: sodium carbonate anhydrous – 20 mg.

Vials (1) – cardboard packs.
Vials (5) – cardboard boxes (for hospitals).
Vials (10) – cardboard boxes (for hospitals).
Vials (50) – cardboard boxes (for hospitals).

Clinical-Pharmacological Group

Antibiotic of the carbapenem group

Pharmacotherapeutic Group

Antibiotic-carbapenem + dehydropeptidase inhibitor

Pharmacological Action

Aquapenem consists of two components: imipenem, the first representative of a new class of beta-lactam antibiotics – thienamycins, and cilastatin – a specific enzyme inhibitor that inhibits the metabolism of imipenem in the kidneys and significantly increases the concentration of unchanged imipenem in the urinary tract. Cilastatin has no intrinsic antibacterial activity and does not inhibit bacterial beta-lactamase.

Aquapenem inhibits the synthesis of the bacterial cell wall and has a bactericidal effect against a wide range of gram-positive and gram-negative microorganisms, aerobic and anaerobic.

The drug’s resistance to destruction by bacterial beta-lactamase makes it effective against many microorganisms such as Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa, Serratia spp., Enterobacter spp., which are resistant to most beta-lactam antibiotics, as well as anaerobes (Bacteroides fragilis). The antibacterial spectrum includes almost all clinically significant pathogenic microorganisms.

Active against the following microorganisms in vitro, as well as in vivo: gram-negative aerobes (Acinetobacter spp., Citrobacter spp., Enterobacter spp., Escherichia coli, Gardnerella vaginalis, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella spp., Morganella morganii, Proteus vulgaris, Providencia rettgeri, Pseudomonas aeruginosa, Serratia spp., including Serratia marcescens); gram-positive aerobes (Enterococcus faecalis, Staphylococcus aureus (including penicillinase-producing strains), Staphylococcus epidermidis (including penicillinase-producing strains), Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes); gram-negative anaerobes (Bacteroides spp., including Bacteroides fragilis, Fusobacterium spp.); gram-positive anaerobes (Bifidobacterium spp., Clostridium spp., Eubacterium spp., Peptococcus spp., Peptostreptococcus spp., Propionibacterium spp.).

Imipenem has a bactericidal effect in vitro on the following microorganisms: gram-positive aerobes (Bacillus spp., Listeria monocytogenes, Nocardia spp., Staphylococcus saprophyticus, Streptococcus groups C, G and viridans group); gram-negative aerobes (Aeromonas hydrophila, Alcaligenes spp., Capnocytophaga spp., Haemophilus ducreyi, Neisseria gonorrhoeae, including penicillinase-producing strains, Pasteurella spp., Providencia stuartii); gram-negative anaerobes (Prevotella bivia, Prevotella disiens, Prevotella melaninogenica, Veillonella spp.).

Not susceptible Enterococcus faecium, methicillin-resistant Staphylococcus spp., Xanthomonas maltophilia, Pseudomonas cepacia.

Acts synergistically with aminoglycosides in vitro against some strains of Pseudomonas aeruginosa.

Pharmacokinetics

Absorption and Distribution

Maximum concentration (C_max) of imipenem after intravenous (IV) administration at a dose of 250, 500 or 1000 mg is reached within 20 min – 14-24, 21-58 and 41-83 mcg/ml respectively. C_max of cilastatin after IV administration at a dose of 250, 500 or 1000 mg is reached within 20 min – 15-25, 31-49 and 56-80 mcg/ml. Plasma protein binding of imipenem – 20%, cilastatin – 40%. Rapidly and well distributed in most tissues and body fluids. Highest concentrations are achieved in pleural effusion, peritoneal and interstitial fluids and reproductive organs. Found in low concentrations in cerebrospinal fluid (CSF). V_d in adults – 0.23-0.31 l/kg.

Metabolism and Excretion

Blocking of tubular secretion of imipenem by cilastatin leads to inhibition of its renal metabolism and accumulation in urine unchanged.

Cilastatin is metabolized to an N-acetyl compound. After IV administration, the half-life (T_1/2) of imipenem and cilastatin in adults is 1 h.

Excreted mainly by the kidneys (70-76% within 10 h) by glomerular filtration (2/3) and active tubular secretion (1/3); 1-2% is excreted via the gastrointestinal tract and 20-25% – by non-renal pathways (mechanism unknown).

Rapidly and effectively (73-90%) removed by hemodialysis (75% of the administered dose is removed as a result of a 3-hour session of intermittent hemofiltration).

Pharmacokinetics in Special Patient Groups

V_d in children aged 2-12 years – 0.7 l/kg, in newborns – 0.4-0.5 l/kg.

After IV administration, the half-life (T_1/2) of imipenem and cilastatin in children aged 2-12 years is 1-1.2 h, in newborns T_1/2 of imipenem is 1.7-2.4 h, cilastatin is 3.8-8.4 h.

In case of renal impairment T_1/2 of imipenem is 2.9-4 h, cilastatin is 13.3-17.1 h.

Indications

Infectious and inflammatory diseases caused by microorganisms sensitive to imipenem

• Lower respiratory tract infections caused by Streptococcus pneumoniae, Staphylococcus aureus (penicillinase-producing strains), Acinetobacter spp., Enterobacter spp., Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella spp., Serratia marcescens;
• Urinary tract infections (complicated and uncomplicated) caused by Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Enterobacter spp., Escherichia coli, Klebsiella spp., Morganella morganii, Proteus vulgaris, Providencia rettgeri, Pseudomonas aeruginosa;
• Intra-abdominal infections caused by Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Staphylococcus epidermidis, Citrobacter spp., Enterobacter spp., Escherichia coli, Klebsiella spp., Morganella morganii, Proteus spp., Pseudomonas aeruginosa, Bifidobacterium spp., Clostridium spp., Eubacterium spp., Peptococcus spp., Peptostreptococcus spp., Propionibacterium spp., Bacteroides spp., including Bacteroides fragilis, Fusobacterium spp.;
• Skin and soft tissue infections caused by Streptococcus pyogenes, Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Staphylococcus epidermidis, Acinetobacter spp., Citrobacter spp., Enterobacter spp., Escherichia coli, Klebsiella spp., Morganella morganii, Proteus vulgaris, Providencia rettgeri, Pseudomonas aeruginosa, Serratia spp., Peptococcus spp., Peptostreptococcus spp., Bacteroides spp., including Bacteroides fragilis, Fusobacterium spp.;
• Bone and joint infections caused by Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Staphylococcus epidermidis, Enterobacter spp., Pseudomonas aeruginosa;
• Bacterial septicemia caused by Streptococcus pneumoniae, Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Enterobacter spp., Escherichia coli, Klebsiella spp., Pseudomonas aeruginosa, Serratia spp., Bacteroides spp., including Bacteroides fragilis;
• Endocarditis caused by Staphylococcus aureus (penicillinase-producing strains);
• Gynecological infections caused by Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Staphylococcus epidermidis, Streptococcus agalactiae (group B streptococci), Enterobacter spp., Escherichia coli, Gardnerella vaginalis, Klebsiella spp., Proteus spp., Bifidobacterium spp., Peptococcus spp., Peptostreptococcus spp., Propionibacterium spp., Bacteroides spp., including Bacteroides fragilis.

Prophylaxis of postoperative complications in at-risk patients with a high probability of developing postoperative infectious complications, as well as in patients with a high risk of intraoperative infection during surgery.

ICD codes

Dosage Regimen

Intravenous infusion.

The doses given below are calculated for adult patients with a body weight of 70 kg or more and a CC of 70 ml/min/1.73 m² or more. For patients with CC less than 70 ml/min/1.73 m² and/or lower body weight, the dose should be proportionally reduced. The dosing recommendations indicate the amount of imipenem to be administered. Administration is divided into several doses.

Average therapeutic dose for adults (calculated by imipenem) – 1-2 g/day, divided into 3-4 administrations; maximum daily dose – 4 g or 50 mg/kg, whichever is the lower dose.

Patients over 12 years with cystic fibrosis were prescribed up to 90 mg/kg/day, but not more than 4 g/day.

For adult patients with mild severity of infection – 250 mg 4 times/day (total daily dose 1 g), moderate severity – 500 mg 3 times/day or 1 g 2 times/day (total daily dose 1.5-2 g), severe severity (highly sensitive strains) – 500 mg 4 times/day (total daily dose 2 g), for severe severity (less sensitive strains, primarily Pseudomonas aeruginosa), for life-threatening infection – 1 g 3-4 times/day (total daily dose 3-4 g).

Each 250-500 mg is administered IV over 20-30 min, and each 750-1000 mg – over 40-60 min. If nausea occurs during administration, the infusion rate of the drug should be reduced.

For prophylaxis of postoperative infections in adult patients – 1 g during induction anesthesia and 1 g – after 3 h. In case of surgery with a high risk of infection development (surgery on the colon and rectum), an additional 500 mg is administered after 8 and 16 h from induction anesthesia.

For adult patients with impaired renal function (CC less than 70 ml/min/1.73 m²) or/and with body weight less than 70 kg, it is first necessary to determine the total daily dose depending on the severity of the infection, corresponding to that for adult patients with body weight >70 kg and without chronic renal failure. Then select the appropriate reduced dose based on the daily dose, CC and body weight of the given patient.

Maximum daily doses for IV administration in adult patients (body weight >70 kg) with renal failure depending on the severity of infection and CC values (ml/min/1.73 m²)

• Maximum daily dose 1 g: CC 41-70 ml/min – 250 mg every 8 h, CC 21-40 ml/min – 250 mg every 12 h, CC 6-20 ml/min – 250 mg every 12 h;
• Maximum daily dose 1.5 g: CC 41-70 ml/min – 250 mg every 6 h, CC 21-40 ml/min – 250 mg every 8 h, CC 6-20 ml/min – 250 mg every 12 h;
• Maximum daily dose 2 g: CC 41-70 ml/min – 500 mg every 8 h, CC 21-40 ml/min – 250 mg every 6 h, CC 6-20 ml/min – 250 mg every 12 h;
• Maximum daily dose 3 g: CC 41-70 ml/min – 500 mg every 6 h, CC 21-40 ml/min – 500 mg every 8 h, CC 6-20 ml/min – 500 mg every 12 h;
• Maximum daily dose 4 g: CC 41-70 ml/min – 750 mg every 8 h, CC 21-40 ml/min – 500 mg every 6 h, CC 6-20 ml/min – 500 mg every 12 h.

The dosing regimen for adult patients with impaired renal function and/or body weight less than 70 kg is given below.

A) Maximum daily dose 1 g

In adult patients with CC less than 5 ml/min, the drug should be used only if hemodialysis is performed no later than 48 hours after the drug infusion. Administration to such patients is recommended only in cases where the benefit of its use outweighs the potential risk of seizures. When treating adult patients with CC less than 5 ml/min, on hemodialysis, doses for adult patients with CC 6-20 ml/min and/or body weight less than 70 kg should be used. The drug is administered after the hemodialysis session and then at 12-hour intervals from the end of the procedure, with careful monitoring of adult patients (especially if they have CNS diseases).

Currently, there is insufficient data to recommend the use of the drug in adult patients on peritoneal dialysis.

Currently, there is insufficient data on the dosing regimen for preoperative prophylaxis in adult patients with CC less than 70 ml/min/1.73 m².

Given the reduced functions of the cardiovascular system, liver, kidneys characteristic of elderly patients, as well as the presence of concomitant diseases and concomitant drug therapy, the lower limits of the recommended doses should be followed when selecting the dose. The condition of the kidneys in elderly patients cannot be fully determined solely by measuring blood urea nitrogen or creatinine. Determination of CC is recommended for dose selection in such patients.

Children with a body weight of 40 kg and more are prescribed the same doses as adults. Children over 3 months of age and with a body weight of less than 40 kg – 15 mg/kg 4 times/day; maximum daily dose – 2 g.

Rules for Solution Preparation

The following solvents are used for the preparation of the infusion solution: 0.9% sodium chloride solution, 5% dextrose solution, 10% dextrose solution, 5% dextrose and 0.9% sodium chloride solution, 5% dextrose and 0.45% sodium chloride solution, 5% dextrose and 0.225% sodium chloride solution, 5% dextrose and 0.15% potassium chloride solution, 5% and 10% mannitol solution at a ratio of 500 mg of imipenem per 100 ml of solvent. The concentration of imipenem in the resulting solution is 5 mg/ml.

20 ml vials

When using the drug in 20 ml vials, the vial contents are first dissolved in 10 ml of a suitable solvent. The resulting solution cannot be used for administration!

After dilution, the solution is shaken well and then transferred to a bottle or container with the remaining part of the solvent (90 ml). The total volume of the solvent is 100 ml. For complete transfer of the drug (residues of the drug on the walls of the 20 ml vial), 20 ml of the previously obtained solution is added to the vial, shaken well, and transferred again to the bottle or container with the already obtained solution. Only after this is the solution ready for use. The concentration of imipenem in the resulting solution is 5 mg/ml.

100 ml vials

When using the drug in 100 ml vials, the vial contents are dissolved in 100 ml of a suitable solvent. The concentration of imipenem in the resulting solution is 5 mg/ml.

Adverse Reactions

From the CNS encephalopathy, tremor, confusion, myoclonus, paresthesia, vertigo, headache, mental disorders including hallucinations, seizures.

From the urinary system oliguria, anuria, polyuria, proteinuria, erythrocyturia, leukocyturia, cylindruria, increased bilirubin concentration in urine and change in urine color, increased plasma concentration of urea nitrogen and creatinine, acute renal failure.

From the gastrointestinal tract nausea, vomiting, diarrhea, pseudomembranous colitis, hemorrhagic colitis, hepatitis (including fulminant), hepatic failure, jaundice, gastroenteritis, abdominal pain, glossitis, hypertrophy of the tongue papillae, staining of teeth or tongue, pharyngeal pain, hypersalivation, heartburn.

From the hematopoietic organs and hemostasis system pancytopenia, bone marrow hematopoiesis suppression, hemolytic anemia, eosinophilia, leukopenia, neutropenia, agranulocytosis, thrombocytopenia, thrombocytosis, monocytosis, lymphocytosis, leukocytosis, basophilia, decrease in hemoglobin and hematocrit, prolongation of prothrombin time.

Laboratory parameters increased activity of hepatic transaminases and alkaline phosphatase, hyperbilirubinemia, increased concentration of low-density lipoproteins, false-positive direct Coombs test, hyponatremia, hyperkalemia, hypochloremia.

Allergic reactions skin rash, itching, urticaria, multiforme exudative erythema (including Stevens-Johnson syndrome), angioneurotic edema, toxic epidermal necrolysis, exfoliative dermatitis, fever, anaphylactic reactions.

From the sense organs hearing loss, ringing in the ears, taste disturbance.

From the respiratory system chest discomfort, dyspnea, hyperventilation.

From the cardiovascular system palpitations, tachycardia.

Local reactions skin hyperemia, painful infiltration at the injection site, phlebitis/thrombophlebitis, infection at the injection site, vein induration.

Other candidiasis, cyanosis, hyperhidrosis, pain in the thoracic spine.

Contraindications

• Chronic renal failure (creatinine clearance less than 5 ml/min without hemodialysis);
• Early childhood (under 3 months);
• In children – severe renal failure (serum creatinine concentration greater than 2 mg/dl);
• Hypersensitivity to imipenem and/or cilastatin, other carbapenems and beta-lactam antibiotics and other components of the drug.

With caution diseases of the CNS, history of seizures, high seizure potential, anticonvulsant therapy with valproic acid (reduction in therapy efficacy); chronic renal failure (creatinine clearance less than 70 ml/min), patients on hemodialysis; elderly age; patients with a history of gastrointestinal diseases (including pseudomembranous colitis).

Use in Pregnancy and Lactation

The use of the drug during pregnancy is acceptable only if the potential benefit of treatment for the mother outweighs the potential risk to the fetus.

Both imipenem and cilastatin are excreted in small amounts in breast milk, so the issue of discontinuing breastfeeding during treatment with the drug should be considered.

Use in Renal Impairment

Contraindicated in chronic renal failure (creatinine clearance less than 5 ml/min without hemodialysis).

When treating adult patients with creatinine clearance less than 5 ml/min, on hemodialysis, doses for adult patients with creatinine clearance of 6-20 ml/min and/or body weight less than 70 kg should be used. The drug is administered after a hemodialysis session and then at 12-hour intervals from the end of the procedure, with adult patients requiring careful monitoring (especially if they have CNS diseases).

In adult patients with impaired renal function (creatinine clearance less than 70 ml/min/1.73 m²) or/and with a body weight of less than 70 kg, it is first necessary to determine the total daily dose depending on the severity of the infection, corresponding to that for adult patients with a body weight >70 kg and without chronic renal failure. Then, select the appropriate reduced dose based on the daily dose, creatinine clearance, and body weight of the given patient.

Pediatric Use

The use of the drug is contraindicated in early childhood (under 3 months) and in children with severe renal failure (serum creatinine concentration greater than 2 mg/dl).

Geriatric Use

Considering the reduced functions of the cardiovascular system, liver, and kidneys characteristic of elderly patients, as well as the presence of concomitant diseases and concomitant drug therapy, the selection of the dose should adhere to the lower limits of the recommended doses. The condition of the kidneys in elderly patients cannot be fully determined solely based on measuring blood urea nitrogen or creatinine levels. For dose selection in such patients, determination of creatinine clearance is recommended.

Special Precautions

The intravenous route of administration is preferable to use in the initial stages of therapy for bacterial septicemia, endocarditis, severe and life-threatening infections, including lower respiratory tract infections caused by Pseudomonas aeruginosa, and in case of severe complications.

Not recommended for the treatment of meningitis.

Stains urine a reddish color (safe and should not be mistaken for hematuria).

Before starting therapy, a thorough history should be taken regarding previous allergic reactions to beta-lactam antibiotics. If an allergic reaction develops, the drug should be discontinued immediately.

In patients with a history of gastrointestinal diseases (especially colitis), there is an increased risk of developing pseudomembranous colitis.

Antiepileptic drug therapy in patients with head trauma or a history of seizures should continue throughout the entire period of treatment with the drug (to avoid CNS side effects).

It should be borne in mind that elderly patients are likely to have age-related renal function impairment, which may require a dose reduction. Monitoring of renal excretory function is advisable.

When using the drug, both during administration and 2-3 weeks after cessation of treatment, diarrhea caused by Clostridium difficile (pseudomembranous colitis) may develop. In mild cases, discontinuation of treatment and the use of ion-exchange resins (cholestyramine, colestipol) is sufficient; in severe cases, replacement of fluid, electrolyte, and protein losses, and the administration of vancomycin, bacitracin, or metronidazole is indicated. Drugs that inhibit intestinal peristalsis should not be used.

The drug contains 37.5 mg of sodium (1.6 mEq) per 1 vial.

As with other beta-lactam antibiotics, Pseudomonas aeruginosa can acquire resistance to imipenem quite quickly. Therefore, during treatment, it is necessary to periodically determine the susceptibility of Pseudomonas aeruginosa to the antibiotic according to the clinical situation.

To prevent the development of resistance and maintain the effectiveness of imipenem in clinical practice, the drug should be used only for the treatment of infections caused by microorganisms proven (or presumably) susceptible to imipenem.

Effect on ability to drive vehicles and operate machinery

Given the likelihood of developing CNS side effects, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions. If CNS side effects occur, one should refrain from performing these activities.

Overdose

Symptoms dose-dependent side effects are intensified.

Treatment in case of overdose, discontinuation of the drug and administration of symptomatic and supportive therapy are recommended. Imipenem and cilastatin are removed by hemodialysis. However, the effectiveness of this procedure in case of drug overdose is unknown.

Drug Interactions

The drug is pharmaceutically incompatible with lactic acid (lactate) and should not be prepared on the basis of solvents containing it. However, the intravenous drug can be administered through the same infusion system as a solution containing lactate.

When used concomitantly with penicillins and cephalosporins, cross-allergy is possible; exhibits antagonism towards other beta-lactam antibiotics (penicillins, cephalosporins, and monobactams).

When used concomitantly with ganciclovir, the risk of developing generalized seizures increases. These drugs should not be used concomitantly, except in cases where the potential benefits outweigh the possible risk.

Drugs that block tubular secretion slightly increase the plasma concentration and T_1/2 of imipenem (if high concentrations of imipenem are required, the concomitant use of these drugs is not recommended).

When using the drug, the serum concentration of valproic acid decreases, which leads to a reduction in the effectiveness of the ongoing anticonvulsant therapy, therefore, monitoring of the plasma concentration of valproic acid is recommended during the treatment period.

The drug should not be mixed in the same syringe with other antibiotics, while simultaneous (isolated) administration with other antibiotics (aminoglycosides) is permitted.

Storage Conditions

The drug should be stored out of the reach of children, in a dry, light-protected place at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.