Kefpim

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KEFPIM (KEFPIМ)

Composition:

Active substance: cefepime;

1 vial contains cefepime 1000 mg as cefepime hydrochloride;

Excipient: L-arginine.

Pharmaceutical form. Powder for solution for injection.

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

Pharmacotherapeutic group.

Antibacterial agents for systemic use. Cephalosporins. ATC code J01D E01.

Pharmacological Properties

Pharmacodynamics

Cefepime is a broad-spectrum, fourth-generation β-lactam cephalosporin antibiotic intended for parenteral administration. It exerts a bactericidal effect. It is active against Gram-positive and Gram-negative bacteria, including most strains resistant to aminoglycosides or third-generation cephalosporins. Cefepime inhibits the synthesis of bacterial cell wall enzymes. The drug is highly resistant to hydrolysis by β-lactamases, has low affinity for chromosomally encoded β-lactamases, and rapidly penetrates Gram-negative bacterial cells.

Cefepime is active against:

Gram-positive aerobes: Staphylococcus aureus, Staphylococcus epidermidis (including β-lactamase-producing strains), Staphylococcus hominis, Staphylococcus saprophyticus, Streptococcus pyogenes (Group A), Streptococcus agalactiae (Group B), Streptococcus pneumoniae (including strains with intermediate resistance to penicillin – MIC from 0.1 to 0.3 μg/mL), other β-hemolytic streptococci (Groups C, G, F), Streptococcus bovis (Group D), Streptococcus viridans;

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. agglomerans, E. sakazakii; Proteus spp., including P. mirabilis, P. vulgaris; Acinetobacter calcoaceticus (including subspecies Anitratus, Iwoffi); Aeromonas hydrophila; Capnocytophaga spp.; Citrobacter spp., including C. diversus, C. freundii; Campylobacter jejuni; Gardnerella vaginalis; Haemophilus ducreyi; H. influenzae (including β-lactamase-producing strains); H. parainfluenzae; Hafnia alvei; Legionella spp.; Morganella morganii; Moraxella (Branhamella) catarrhalis (including β-lactamase-producing strains); Neisseria gonorrhoeae (including β-lactamase-producing strains); N. meningitidis; Proteus spp. (including P. rettgeri, P. stuartii); Salmonella spp.; Serratia spp. (including S. marcescens, S. liquefaciens); Shigella spp.; Yersinia enterocolitica;

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

Most enterococcal strains and methicillin-resistant staphylococci are resistant to most cephalosporin antibiotics, including cefepime.

Cefepime is not active against certain strains of Xanthomonas (Pseudomonas) maltophilia, Bacteroides fragilis, and Clostridium difficile.

Pharmacokinetics

Maximum plasma concentration of the drug is achieved within 0.5 hours after intravenous administration and within 2 hours after intramuscular administration (1 g dose).

Average therapeutic plasma concentrations of cefepime in healthy adult males at various time points after single intravenous (IV) and intramuscular (IM) administration are presented in the table below.

Average plasma concentrations of cefepime (μg/mL)

Cefepime protein binding to plasma proteins is less than 19% and does not depend on the drug concentration in blood serum. It poorly penetrates the intact blood-brain barrier. However, during meningitis, it reaches therapeutic concentrations in cerebrospinal fluid. Significant concentrations are found in urine, bile, peritoneal fluid, bronchial secretions, and tissues of the gallbladder, appendix, and prostate gland. The volume of distribution is 0.25 L/kg; in children aged 2 months to 16 years, it is 0.33 L/kg. Cefepime is metabolized to N-methylpyrrolidine, which rapidly converts into N-methylpyrrolidine oxide. Cefepime is primarily eliminated via glomerular filtration (total clearance of cefepime is approximately 120 mL/min, mean renal clearance is 110 mL/min). Approximately 85% of the administered dose is excreted unchanged in urine, 1% as N-methylpyrrolidine, approximately 6.8% as N-methylpyrrolidine oxide, and approximately 2.5% as the cefepime epimer. The mean elimination half-life is approximately 2 hours. In volunteers receiving doses up to 2 g intravenously every 8 hours for 9 days, no drug accumulation was observed.

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

In patients with impaired renal function, the elimination half-life is prolonged. The average half-life of cefepime during hemodialysis is 13 hours and during peritoneal dialysis is 19 hours.

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

Clinical characteristics.

Indications.

Adults.

Infections caused by microorganisms sensitive to the drug:

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

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;
• sepsis;
• empirical therapy in patients with febrile neutropenia;
• bacterial meningitis.

Contraindications.

Hypersensitivity to any component of the drug or to cephalosporins, penicillins, and other β-lactam antibiotics.

Interaction with other medicinal products and other types of interactions.

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

To avoid potential drug interactions, cefepime should not be administered simultaneously with metronidazole solutions, vancomycin, gentamicin, tobramycin sulfate, or netilmicin sulfate. When co-administered with these agents, each antibiotic should be administered separately.

Diuretics (such as furosemide) and aminoglycosides reduce tubular secretion of cefepime, increase its serum concentration, prolong its elimination half-life, enhance nephrotoxicity, and increase the risk of nephron necrosis. Concurrent administration of cefepime and aminoglycosides increases the risk of ototoxic effects of the latter.

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.

It is necessary to accurately determine 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, especially drug allergies. If an allergic reaction occurs, the drug should be discontinued. Severe hypersensitivity reactions may require administration of epinephrine, hydrocortisone, antihistamines, and other emergency measures.

During prolonged treatment, it is necessary to regularly monitor liver and kidney function tests and hematopoietic system parameters.

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

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

Use with caution in patients with gastrointestinal disorders, particularly colitis.

Prothrombin time should be monitored.

The dose of the drug should be adjusted in patients with impaired renal function (creatinine clearance < 60 mL/min) to compensate for slower renal elimination. Since prolonged serum antibiotic concentrations may occur at usual doses in patients with renal insufficiency or other conditions that may impair kidney function, such patients require a reduced maintenance dose of cefepime. The degree of renal impairment, severity of infection, and susceptibility of the causative organisms should be considered when determining the subsequent dose.

Serious adverse reactions such as reversible encephalopathy (confusion, including clouding of consciousness), myoclonus, seizures, and/or renal failure have been observed most frequently in patients with renal insufficiency receiving doses exceeding the recommended regimen, and in elderly patients with renal insuff游戏副本

Dosage and Administration.

The medication is intended for parenteral administration. The physician determines the dosage individually depending on the severity of the disease, patient's age, site of infection, and renal function.

The usual dosage for adults and children with body weight above 40 kg is 1 g administered intravenously or intramuscularly every 12 hours. The usual duration of treatment is 7–10 days. Severe infections may require prolonged treatment. Dosage recommendations for cefepime in adults are provided in the table.

For prevention of infections during surgical procedures. Administer 2 g of the drug intravenously over 60 minutes before the start of surgery.

30 minutes. After completion, additionally administer 500 mg of metronidazole intravenously. Metronidazole solutions should not be administered simultaneously with cefepime. The infusion system must be flushed before administration of metronidazole.

During prolonged (more than 12 hours) surgical procedures, a repeat dose of cefepime should be administered 12 hours after the first dose, followed by administration of metronidazole.

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

Recommended doses of cefepime for adults

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

Men:

weight (kg) × (140 − age)

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

72 × serum creatinine (mg/dL)

Women:

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

During hemodialysis, approximately 68% of the drug dose is removed 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 (CAPD), the drug can be administered at the initial standard recommended doses of 500 mg, 1 g, or 2 g, depending on the severity of infection, with a dosing interval of 48 hours.

Children aged 1–2 months should receive the drug only for life-threatening indications. Children weighing less than 40 kg who are receiving cefepime therapy should be closely monitored.

In children with impaired renal function, dosage reduction or increased dosing intervals are 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. Cefepime should be administered only for life-threatening indications at a dose of 30 mg/kg body weight every 12 or 8 hours, depending on the severity of infection.

Children aged 2 months and older. The maximum dose in children should not exceed the recommended adult dose. The usual recommended dose in children weighing less than 40 kg for 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 (every 8 hours in febrile neutropenia and bacterial meningitis). The usual duration of treatment is 7–10 days; severe infections may require longer treatment.

Children weighing 40 kg or more should receive cefepime as in adults.

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

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. Administer intravenously slowly over 3–5 minutes or via an intravenous infusion system.

Intramuscular administration. Cefepime can be reconstituted with sterile water for injection, 0.9% sodium chloride injection solution, 5% dextrose injection solution, bacteriostatic water for injection with parabens, benzyl alcohol, or 0.5% or 1% lidocaine hydrochloride solution, at the concentrations specified in the table below.

The prepared solution of cefepime should be visually inspected for the absence of particulate matter prior to administration.

Reconstituted solutions of the drug for intramuscular and intravenous administration may be stored for up to 24 hours at room temperature or 7 days in the refrigerator (2–8 °C).

Children.

May be used in children aged 1 month and older.

Overdose.

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

Treatment. Administration of the drug should be discontinued and symptomatic therapy initiated. Hemodialysis accelerates 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

Immune system disorders: hypersensitivity reactions, including anaphylaxis, anaphylactic shock, angioedema.

Skin and subcutaneous tissue disorders: skin rashes, erythema, pruritus, urticaria.

Gastrointestinal disorders: nausea, vomiting, oral candidiasis, diarrhea, colitis (including pseudomembranous colitis), constipation, abdominal pain, dyspepsia, altered taste sensation.

Hepatobiliary disorders: hepatitis, cholestatic jaundice.

Nervous system disorders: dizziness, headache, restlessness, insomnia, paresthesia, confusion/loss of consciousness, seizures/epileptiform attacks, myoclonus, encephalopathy, hallucinations, stupor, coma.

General disorders and administration site conditions: increased body temperature, sweating, chest/back pain, asthenia, injection site reactions including inflammation, phlebitis, pain.

Infections: candidiasis, vaginitis, genital pruritus, pseudomembranous colitis, other superinfections.

Respiratory system disorders: respiratory disorders, cough, sore throat, dyspnea.

Cardiovascular system disorders: tachycardia, vasodilation, chest pain, peripheral edema.

Renal and urinary system disorders: renal failure.

Blood and lymphatic system disorders: anemia, eosinophilia, transient leukopenia, neutropenia, agranulocytosis, thrombocytopenia.

Laboratory abnormalities: increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin; prolonged prothrombin time or partial thromboplastin time (PTT); positive Coombs test without hemolysis; transient increase in blood urea nitrogen and/or serum creatinine; pseudopositive glucose in urine test.

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.

2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Incompatibility.

The drug should not be mixed in the same container with other medicinal products except for the solvents specified in the section "Dosage and administration".

Packaging.

1000 mg of powder in a vial; 1 vial per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

Astral SteriTech Private Limited.

Manufacturer's address and place of business.

911, G.I.D.C., Makarpura, Vadodara, Gujarat 390 010, India.