Cefimek

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

Composition:

Active substance: cefepime;

1 vial contains cefepime hydrochloride equivalent to 1000 mg of cefepime;

Excipient: L-arginine.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical characteristics: powder from white to light yellow color.

Pharmacotherapeutic group.

Antibacterial agents for systemic use. Cephalosporins.

ATC Code J01D E01.

Pharmacological Properties

Pharmacodynamics

Cefepime is a broad-spectrum β-lactam cephalosporin antibiotic of the fourth generation intended for parenteral administration. It exerts a bactericidal effect. It is active against both Gram-positive and Gram-negative bacteria, including most strains resistant to aminoglycosides or third-generation cephalosporin antibiotics. Cefepime inhibits the synthesis of enzymes involved in the bacterial cell wall formation. The drug is highly resistant to hydrolysis by β-lactamases, has low affinity for chromosomally encoded β-lactamases, and rapidly penetrates into 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 – minimal inhibitory concentration (MIC) from 0.1 to 0.3 mcg/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; Providencia 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 microorganisms belonging to Bacteroides; Clostridium perfringens; Fusobacterium spp.; Mobiluncus spp.; Peptostreptococcus spp.; Veillonella spp.

Most Enterococcus strains and methicillin-resistant Staphylococcus strains are resistant to most cephalosporin antibiotics, including cefepime.

Cefepime is inactive 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 (i.v.) and intramuscular (i.m.) administration are presented in the table below.

Average plasma concentrations of cefepime (mcg/mL)

Protein binding of cefepime 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 inflammation of the meninges, therapeutic concentrations are achieved in cerebrospinal fluid. High 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 to N-methylpyrrolidine oxide. Cefepime is primarily eliminated by glomerular filtration (total clearance of cefepime is approximately 120 mL/min, with mean renal clearance being 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 epimer of cefepime. 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.

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

In patients with impaired renal function, the elimination half-life is prolonged. On average, the 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 required for such patients.

Clinical characteristics.

Indications.

Adults.

Infections caused by microorganisms sensitive to Cefimek, namely:

• respiratory tract infections (including hospital-acquired and community-acquired pneumonia, acute bronchitis, and exacerbations of chronic 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 (both complicated, e.g. pyelonephritis, and uncomplicated);
• 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 antibiotics, 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 solution; 5% and 10% glucose injection solution; 6M sodium lactate injection solution; 5% glucose and 0.9% sodium chloride injection solution; Ringer's lactate solution with 5% glucose injection solution.

To avoid potential drug interactions, Cefimek should not be administered simultaneously with metronidazole, vancomycin, gentamicin, tobramycin sulfate, or netilmicin sulfate solutions. 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 elimination half-life, enhance nephrotoxicity, and increase the risk of nephronecrosis. Concomitant administration of cefepime and aminoglycosides increases the risk of ototoxic effects of the latter.

Effect on laboratory test results.

Cefepime administration may result in 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 essential to determine precisely 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, administration of the drug must be discontinued. Severe hypersensitivity reactions may require administration of epinephrine, hydrocortisone, antihistamines, and other emergency measures.

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

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

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. 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.

Patients with impaired renal function (creatinine clearance < 60 mL/min) require dose adjustment to compensate for reduced renal elimination. Since prolonged antibiotic exposure in serum may occur at standard doses in patients with renal impairment or other conditions that may worsen 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 considered when determining the subsequent dose.

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

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

Broad-spectrum antibiotics, particularly 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 monitored. Mild forms of colitis may resolve spontaneously after discontinuation of therapy, while moderate to severe cases may require specific treatment.

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

It is unlikely that prescribing cefepime in the absence of proven or suspected bacterial infection or for prophylactic use will be beneficial, but it increases the risk of developing bacteria resistant to this drug. Prolonged use of cefepime (as with other antibiotics) may lead to superinfection. Re-evaluation of the patient's condition is necessary. If superinfection develops, appropriate therapeutic measures should be initiated.

Many cephalosporins, including cefepime, are associated with reduced prothrombin activity. High-risk patients include those with impaired liver or kidney function, 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 be obtained. When performing hematological or transfusion procedures involving cross-matching blood using the antiglobulin test, or during Coombs' testing in newborns whose mothers received cephalosporin antibiotics before delivery, it should be considered that a positive Coombs' test may be due to the drug.

When using lidocaine as a solvent in pediatric patients, safety information regarding lidocaine should be taken into account.

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

Use during pregnancy or breastfeeding.

Adequate and well-controlled studies on the use of the drug in pregnant women have not been conducted; therefore, cefepime should be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus.

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

Ability to affect reaction speed when driving or operating machinery.

Not studied. If dizziness or other adverse reactions that may affect reaction speed occur, patients should refrain from driving or operating machinery.

Dosage and Administration

The medicinal product is intended for parenteral administration. The dose of the drug is determined individually by a physician 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 over 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. Dosing 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 30 minutes to adults, 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 of cefepime equal to the initial dose is recommended 12 hours after the first dose, followed by administration of metronidazole.

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

Recommended doses of cefepime for adults

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

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 (CAPD), the drug may be administered at the usual initial recommended doses of 500 mg, 1 g, or 2 g, depending on the severity of infection, at 48-hour intervals.

In children aged 1–2 months, the drug should be administered only for 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 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. Cefimek 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 for children should not exceed the recommended adult dose. The usual recommended dose for children weighing less than 40 kg in cases of 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 for patients with febrile neutropenia or 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 in the same manner as adults.

Administration of the drug. Cefimek 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 indicated in the table below. It should be administered intravenously slowly over 3–5 minutes or via an intravenous infusion system.

Intramuscular administration. Cefepime can 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 specified in the table below.

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

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

Children.

To be used in children aged 1 month and older.

Overdose.

Symptoms: In cases of significant exceeding the recommended doses, side effects may become more pronounced, especially in patients with impaired renal function. 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 adrenaline and other forms of intensive therapy.

Adverse reactions.

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

Skin side effects: skin rashes, erythema, pruritus, urticaria.

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

Hepatobiliary system side effects: hepatitis, cholestatic jaundice.

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

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

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

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

Cardiovascular system side effects: tachycardia, vasodilation, chest pain, peripheral edema.

Urinary system side effects: renal failure.

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

Laboratory findings: increased levels of alanine aminotransferase, aspartate aminotransferase, 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; false-positive urine glucose test.

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

Shelf life. 3 years (from the date of manufacture of the bulk form).

Storage conditions.

Store in a light-protected and child-inaccessible place at a temperature not exceeding 25 °C. Prepared solutions for intramuscular and intravenous administration may be stored for up to 24 hours at room temperature or for up to 7 days in a refrigerator (2–8 °C).

Incompatibility.

Do not mix with other medicinal products in the same container. Use only solvents specified in the sections "Administration and dosage" and "Interaction with other medicinal products and other types of interactions".

Packaging.

20 mL glass vials stoppered with rubber closures and sealed with aluminum caps. Packs of 25 or 50 vials. For pack size No. 1: one vial in a cardboard box.

Prescription status. Prescription only.

Manufacturer. LLC "AVANT" (packaging of the bulk form produced by "SUNCE Laboratories Pvt. Ltd.", India).

Manufacturer's address and location of business activity.

14 Anton Tsydika Street, Kyiv, 03057, Ukraine.

Phone/fax: (044) 496-19-94; e-mail: [email protected]