Espim

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

Composition:

Active substance: cefepime;

1 vial contains cefepime hydrochloride 1.2 g, equivalent to cefepime 1.0 g;

Excipient: L-arginine.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: almost white crystalline powder.

Pharmacotherapeutic group.

Antibacterial agents for systemic use. β-lactam antibiotics.

ATC code J01D E01.

Pharmacological properties.

Pharmacodynamics.

Cefepime inhibits the synthesis of bacterial cell wall enzymes and has a broad spectrum of activity against various gram-positive and gram-negative bacteria. The drug is highly resistant to hydrolysis by most β-lactamases, has low affinity for chromosomally mediated β-lactamases, and rapidly penetrates gram-negative bacterial cells.

Cefepime is active against the following microorganisms:

Gram-positive aerobes: Staphylococcus aureus and Staphylococcus epidermidis (including β-lactamase-producing strains); other staphylococcal strains, including S. hominis, S. saprophyticus; Streptococcus pyogenes (group A streptococci); Streptococcus agalactiae (group B streptococci); Streptococcus pneumoniae (including strains with intermediate penicillin resistance − MIC from 0.1 to 1 mcg/mL); other β-hemolytic streptococci (groups C, G, F); S. bovis (group D); Viridans group streptococci. (Most enterococcal strains, e.g., Enterococcus faecalis, and methicillin-resistant staphylococci are resistant to most cephalosporin antibiotics, including cefepime.)

Gram-negative aerobes: Pseudomonas spp., including P. aeruginosa, P. putida, P. stutzeri; Escherichia coli; Klebsiella spp., including K. pneumoniae, K. oxytoca, K. ozaenae; Enterobacter spp., including E. cloacae, E. aerogenes, E. sakazakii; Proteus spp., including P. mirabilis, P. vulgaris; Acinetobacter calcoaceticus (subsp. anitratus, lwoffi); Aeromonas hydrophila; Capnocytophaga spp.; Citrobacter spp., including C. diversus, C. freundii; Campylobacter jejuni; Gardnerella vaginalis; Haemophilus ducreyi; H. influenzae (including β-lactamase-producing strains); Haemophilus parainfluenzae; Hafnia alvei; Legionella spp.; Morganella morganii; Moraxella catarrhalis (Branhamella catarrhalis) (including β-lactamase-producing strains); Neisseria gonorrhoeae (including β-lactamase-producing strains); N. meningitidis; Pantoea agglomerans (formerly known as Enterobacter agglomerans); Providencia spp. (including P. rettgeri, P. stuartii); Salmonella spp.; Serratia spp. (including S. marcescens, S. liquefaciens); Shigella spp.; Yersinia enterocolitica.

(Cefepime is inactive against many strains of Xanthomonas maltophilia and Pseudomonas maltophilia.)

Anaerobes: Bacteroides spp., including B. melaninogenicus and other oral cavity microorganisms belonging to Bacteroides; Clostridium perfringens; Fusobacterium spp.; Mobiluncus spp.; Peptostreptococcus spp.; Veillonella spp.

(Cefepime is inactive against Bacteroides fragilis and Clostridium difficile.)

Pharmacokinetics.

Mean plasma concentrations of cefepime in healthy adult males at various time points after single intravenous and intramuscular administration are presented in the table below.

Plasma concentrations of cefepime (mcg/mL) following intravenous (IV) and intramuscular (IM) administration.

Therapeutic concentrations of cefepime are also achieved in urine, bile, peritoneal fluid, bronchial mucosal secretions, sputum, prostate, appendix, and gallbladder.

The average elimination half-life of cefepime is approximately 2 hours. In healthy volunteers receiving doses up to 2 g intravenously every 8 hours for 9 days, no drug accumulation was observed.

Cefepime is metabolized to N-methylpyrrolidine, which is rapidly converted to N-methylpyrrolidine oxide. The average total clearance is 120 mL/min. Cefepime is primarily eliminated by the kidneys mainly through glomerular filtration (average renal clearance – 110 mL/min). Approximately 85% of the administered dose is excreted in urine as unchanged cefepime, 1% as N-methylpyrrolidine, about 6.8% as N-methylpyrrolidine oxide, and about 2.5% as cefepime epimer. Protein binding of cefepime to plasma proteins is less than 19% and is independent of drug concentration in serum.

Dose adjustment is not required in patients aged 65 years and older with normal renal function, despite their lower renal clearance compared to younger patients.

Studies conducted in patients with various degrees of renal impairment have demonstrated an increased elimination half-life. The average half-life in patients with severe renal dysfunction requiring dialysis is 13 hours with hemodialysis and 19 hours with peritoneal dialysis.

The pharmacokinetics of cefepime are not altered in patients with hepatic dysfunction or cystic fibrosis. Dose adjustment in such patients is not necessary.

Dosage regimen: 50 mg/kg body weight administered intravenously over 5 to 20 minutes every 8 hours.

Clinical characteristics.

Indications.

Adults.

Infections caused by microorganisms sensitive to the drug:

• respiratory tract infections, including pneumonia, bronchitis;
• skin and soft tissue infections;
• intra-abdominal infections, including peritonitis and biliary tract infections;
• gynecological infections;
• septicemia.

Empirical therapy in patients with febrile neutropenia.

Prophylaxis of postoperative complications in intra-abdominal surgery.

Children.

• Pneumonia;
• urinary tract infections, including pyelonephritis;
• skin and soft tissue infections;
• septicemia;
• empirical therapy in patients with febrile neutropenia;
• bacterial meningitis.

Contraindications.

Hypersensitivity to cefepime or L-arginine, as well as to cephalosporin-class antibiotics, penicillins, or other β-lactam antibiotics.

Interaction with other medicinal products and other forms of interactions.

When administering high doses of aminoglycosides concomitantly with cefepime, renal function should be closely monitored due to the potential nephrotoxicity and ototoxicity of aminoglycoside antibiotics. Nephrotoxicity has been observed after concomitant administration of other cephalosporins with diuretics such as furosemide.

Cefepime at concentrations ranging from 1 to 40 mg/mL is compatible with the following parenteral solutions: 0.9% sodium chloride injection; 5% and 10% dextrose injection; 6% sodium lactate injection; 5% dextrose and 0.9% sodium chloride injection; Ringer's lactate with 5% dextrose injection.

To avoid potential drug interactions with other agents, cefepime solutions (as with most other β-lactam antibiotics) should not be administered simultaneously with metronidazole, vancomycin, gentamicin, tobramycin sulfate, or netilmicin sulfate solutions. If co-administration of cefepime with any of these agents is necessary, each antibiotic should be administered separately.

Effect on laboratory test results. Cefepime may cause false-positive glucose in urine tests when using Benedict's reagent. It is recommended to use glucose tests based on enzymatic glucose oxidation reactions.

Special precautions for use.

In patients at high risk of severe infections (e.g., patients with a history of bone marrow transplantation associated with reduced marrow activity due to severe malignant hemolytic disorders with severe progressive neutropenia), monotherapy may be insufficient, and combination antimicrobial therapy is indicated.

When cefepime is used, as with other drugs in this class, serious adverse reactions such as reversible encephalopathy (confusion, including clouding of consciousness), myoclonia, seizures, and/or renal failure have been observed most frequently in patients with renal impairment who received doses exceeding the recommended dosage regimen, and in elderly patients with renal impairment receiving recommended doses of cefepime. Some cases occurred in patients who received doses adjusted according to renal function. In most cases, symptoms of nephrotoxicity were reversible and resolved after discontinuation of cefepime and/or after hemodialysis.

It is essential to determine carefully whether the patient has previously experienced immediate-type hypersensitivity reactions to cefepime, cephalosporins, penicillins, or other β-lactam antibiotics. Antibiotics should be administered with caution to all patients with any form of allergy, particularly to drugs. If an allergic reaction occurs, the drug should be discontinued. Severe immediate-type hypersensitivity reactions may require administration of epinephrine and other therapeutic interventions.

Use with caution in patients with gastrointestinal disorders, particularly colitis. Broad-spectrum antibiotics, especially when used long-term, may cause pseudomembranous colitis ranging in severity from mild diarrhea to fatal colitis; therefore, the occurrence of diarrhea during cefepime therapy should be closely monitored. Mild forms of colitis may resolve spontaneously after completion of therapy, while moderate or severe cases may require specific treatment.

Administration of antibacterial agents alters the normal flora of the colon and may lead to overgrowth of Clostridium difficile. Studies indicate that the toxin produced by Clostridium difficile is the primary cause of antibiotic-associated colitis. Once pseudomembranous colitis is diagnosed, appropriate measures should be taken. Cases of mild pseudomembranous colitis may resolve after discontinuation of the drug. In moderate and severe cases, consideration should be given to the need for fluid and electrolyte replacement, protein supplementation, and administration of an antibacterial agent effective against Clostridium difficile.

As with other antibiotics, use of the drug may lead to superinfection, and appropriate therapeutic measures should be taken.

Prothrombin time should be monitored.

During prolonged treatment, regular monitoring of liver and kidney function and hematopoietic parameters is necessary.

The pharmacokinetics of cefepime in patients with hepatic impairment are not altered. Dose adjustment is not required in such patients.

In patients with impaired renal function (creatinine clearance < 60 mL/min), the dose should be adjusted to compensate for reduced renal elimination. Since prolonged antibiotic serum concentrations may occur with standard doses in patients with renal impairment or other conditions that may impair renal function, the maintenance dose should be reduced when administering cefepime to such patients. The degree of renal impairment, severity of infection, and susceptibility of the causative organisms should be taken into account when determining the subsequent dose.

For patients aged 65 years and older with normal renal function, dose adjustment of cefepime is not required, despite lower renal clearance compared to younger patients. However, elderly patients may have reduced renal function; therefore, caution should be exercised when selecting the dose, and renal function should be monitored.

Many cephalosporins, including cefepime, have been associated with reduced prothrombin activity. High-risk patients include those with hepatic or renal impairment, malnourished patients, and those receiving prolonged courses of antimicrobial therapy. Prothrombin should be monitored in high-risk patients, and vitamin K should be administered if necessary.

During cefepime therapy, positive results in the direct Coombs' test may occur. When performing hematological or transfusion procedures involving blood grouping by the cross-matching method, or when performing the Coombs' test in newborns whose mothers received cephalosporin antibiotics before delivery, it should be considered that a positive Coombs' test may be due to drug administration.

It has been demonstrated that L-arginine alters glucose metabolism and simultaneously increases serum glucose and calcium levels when administered at doses 33 times higher than the maximum recommended dose of cefepime. The effect at lower doses is currently unknown.

Use during pregnancy or breastfeeding.

The drug may be administered during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

Cefepime is excreted in breast milk in very small amounts; therefore, breastfeeding should be discontinued during treatment with the drug.

Ability to affect reaction speed when driving or operating machinery.

Not studied. If dizziness or other adverse reactions occur, patients should refrain from driving or operating machinery.

Method of Administration and Dosage.

Before administering the drug, a skin sensitivity test should be performed.

The usual dosage for adults is 1 g, administered intravenously or intramuscularly every 12 hours. The typical duration of treatment is 7–10 days; severe infections may require longer treatment.

However, dosage and route of administration may vary depending on the susceptibility of the causative microorganisms, the severity of the infection, and the patient's renal function. Dosage recommendations for cefepime in adults are provided in the table.

For the prevention of infections during surgical procedures. Administer 2 g of the drug intravenously over 30 minutes, 60 minutes before the start of surgery. After completion, additionally administer 500 mg of metronidazole intravenously. Metronidazole solutions should not be administered simultaneously with cefepime. The infusion system should be flushed before administering metronidazole.

During prolonged surgical procedures (longer than 12 hours), a repeat dose equal to the initial dose is recommended 12 hours after the first dose, followed by administration of metronidazole.

Renal function impairment. In patients with impaired renal function (creatinine clearance less than 30 mL/min), the dose of the drug must be adjusted.

Recommended doses of cefepime for adults

If only serum creatinine concentration is known, creatinine clearance can be calculated using the formula below:

Men:

body weight (kg) × (140 − age)

creatinine clearance (mL/min) = ---------------------------------------------------;

72 × serum creatinine (mg/dL)

Women:

creatinine clearance (mL/min) = above value × 0.85.

During hemodialysis, approximately 68% of the drug dose is eliminated from the body over 3 hours. After each dialysis session, a supplemental dose equal to the initial dose should be administered. For continuous ambulatory peritoneal dialysis, the drug may be administered at the usual recommended initial doses of 500 mg, 1 g, or 2 g, depending on the severity of infection, with a dosing interval of 48 hours.

The drug should be administered to children aged 1–2 months only under life-threatening indications. The condition of children weighing less than 40 kg receiving cefepime therapy should be closely monitored.

In children with impaired renal function, dose reduction or increased dosing interval is recommended.

Calculation of creatinine clearance in children:

0.55 × height (cm)

creatinine clearance (mL/min/1.73 m²) = ---------------------------------

serum creatinine (mg/dL)

or

0.52 × height (cm)

creatinine clearance (mL/min/1.73 m²) = ------------------------------------------ − 3.6

serum creatinine (mg/dL)

Children aged 1 to 2 months. Esepim should be administered only under life-threatening indications at a dose of 30 mg/kg body weight every 12 or 8 hours, depending on the severity of infection.

Children from 2 months of age. The maximum dose in children should not exceed the recommended adult dose. The usual recommended dose for children weighing less than 40 kg in complicated or uncomplicated urinary tract infections (including pyelonephritis), uncomplicated skin infections, pneumonia, and empirical treatment of febrile neutropenia is 50 mg/kg every 12 hours (for patients with febrile neutropenia and bacterial meningitis – every 8 hours). The usual duration of treatment is 7–10 days; severe infections may require longer treatment.

Children weighing 40 kg or more should receive doses as recommended for adults.

Administration of the drug. Esepim can be administered intravenously or by deep intramuscular injection into a large muscle mass (e.g., the upper outer quadrant of the gluteal muscle – gluteus maximus).

Intravenous administration. The intravenous route is preferred for patients with severe or life-threatening infections.

For intravenous administration, cefepime should be dissolved in sterile water for injection, 5% dextrose injection solution, or 0.9% sodium chloride injection solution, as specified in the table below. It should be administered intravenously slowly over 3–5 minutes or via an intravenous infusion system.

Intramuscular administration. The drug may be dissolved in sterile water for injection, 0.9% sodium chloride injection solution, 5% dextrose injection solution, bacteriostatic water for injection with parabens or benzyl alcohol, or 0.5% or 1% lidocaine hydrochloride solution at the concentrations indicated in the table below.

When lidocaine is used as a solvent, a skin test for tolerance should be performed before administration.

As with other parenterally administered medicinal products, prepared solutions of the drug should be inspected for the presence of particulate matter prior to administration.

Appropriate microbiological investigations should be carried out to identify the causative microorganism(s) and to determine susceptibility to cefepime. However, cefepime may be used as monotherapy prior to identification of the causative microorganism, considering the broad spectrum of antibacterial activity of the drug against Gram-positive and Gram-negative microorganisms. In patients at risk of mixed aerobic/anaerobic infection (including Bacteroides fragilis), treatment with cefepime may be initiated in combination with an agent active against anaerobes, pending identification of the causative organism.

Children.

May be administered to children aged 1 month and older.

Overdose.

Symptoms: In cases of significant overdose, especially in patients with impaired renal function, adverse effects are intensified. Symptoms of overdose include encephalopathy accompanied by hallucinations, disturbances of consciousness, stupor, coma, myoclonus, epileptiform seizures, and neuromuscular excitability.

Treatment: Administration of the drug should be discontinued and symptomatic therapy initiated. Hemodialysis accelerates the elimination of cefepime from the body; peritoneal dialysis is poorly effective. Severe immediate-type allergic reactions require administration of epinephrine and other forms of intensive therapy.

Adverse reactions.

With a frequency of 0.1% to 1%:

Hypersensitivity: pruritus, rash, urticaria;

Gastrointestinal disorders: nausea, vomiting, oral candidiasis, diarrhea, dyspepsia, altered taste sensation, colitis (including pseudomembranous colitis);

Respiratory system: cough, sore throat, dyspnea;

Cardiovascular system: tachycardia;

Central nervous system: headache, insomnia, restlessness, seizures;

Immune system: hypersensitivity reactions, including anaphylaxis, anaphylactic shock, angioneurotic edema;

Hepatobiliary system: hepatitis, cholestatic jaundice;

Other: fever, vaginitis, asthenia, sweating, erythema, chest pain, pain in chest/back, chest pain, peripheral edema, superinfections.

With a frequency of 0.05% to 0.1%: abdominal pain, constipation, vasodilation, respiratory disorders, dizziness, paresthesia, genital pruritus, fever, and candidiasis.

With a frequency less than 0.05%, anaphylaxis and epileptiform seizures were observed.

Local reactions at the site of administration: intravenous – phlebitis and inflammation;

intramuscular – pain, inflammation.

Post-marketing studies:

• Encephalopathy (loss of consciousness, hallucinations, stupor, coma), epileptiform seizures, myoclonia, renal failure;
• anaphylaxis, including anaphylactic shock, transient leukopenia, neutropenia, agranulocytosis, and thrombocytopenia.

Laboratory findings: increased levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, anemia, eosinophilia, prolonged prothrombin time or partial thromboplastin time (PTT), and positive Coombs test without hemolysis, pseudopositive glucose urine test. Transient increases in blood urea nitrogen and/or serum creatinine and transient thrombocytopenia were observed in less than 0.5% of patients. Transient leukopenia and neutropenia were also reported.

In addition to the above-mentioned adverse reactions, adverse reactions typical for cephalosporin antibiotics are possible: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, toxic nephropathy, aplastic anemia, hemolytic anemia, bleeding, liver function disorders, cholestasis, pancytopenia.

Shelf life.

3 years.

Storage conditions.

Store in a place protected from light, out of reach of children, at a temperature not exceeding 25 °C.

The reconstituted solution should be stored protected from light for up to 24 hours at room temperature or up to 7 days at 2–8 °C.

Incompatibility.

Do not mix with other medicinal products in the same container. Use only the solvents specified in the section "Administration and dosage".

Packaging.

1 glass vial with powder in a cardboard box (package No. 1); 10 glass vials with powder in a cardboard box (package No. 10).

Prescription status.

Prescription only.

Manufacturer.

STERIL-GENE LIFE SCIENCES (P) LTD., INDIA /
Steril-Gene Life Sciences (P) Ltd., India.

Manufacturer's address and place of business.

No. 45, Mangalam Main Road, Villianur Commune, Puducherry 605110, India /
No. 45, Mangalam Main Road, Villianur Commune, Puducherry 605110, India.