Cefimek

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEFIMEK

Composition:

Active substance: cefepime;

1 vial contains cefepime hydrochloride equivalent to 500 mg or 1000 mg of cefepime;

Excipient: L-arginine.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white to yellowish powder.

Pharmacotherapeutic group.

Antibacterials for systemic use. Other β-lactam antibiotics. Fourth-generation cephalosporins. Cefepime.

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 bacterial cell wall enzymes. The drug is highly stable against 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), Strept combustiae (including strains with intermediate resistance to penicillin – minimal inhibitory concentration (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; Providencia spp. (including P. rettgeri, P. stuartii); Salmonella spp.; Serratia (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 strains of enterococci and methicillin-resistant staphylococci 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 (dose of 1 g).

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 Table 1.

Table 1

Protein binding of cefepime to plasma proteins is less than 19% and is independent of 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. 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 cefepime clearance is approximately 120 mL/min, with average renal clearance of 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. 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 necessary for such patients.

Clinical characteristics.

Indications.

Adults.

Infections caused by microorganisms sensitive to cefepime:

• respiratory tract infections, including pneumonia;
• uncomplicated skin and soft tissue infections;
• complicated intra-abdominal infections (used in combination with metronidazole);
• uncomplicated and complicated urinary tract infections (including pyelonephritis);
• septicemia;
• empirical therapy in patients with febrile neutropenia;
• prevention of postoperative complications in intra-abdominal surgery.

Children.

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

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 ranging from 1 to 40 mg/mL is compatible with the following parenteral solutions: 0.9% sodium chloride injection solution; 5% and 10% glucose injection solutions; 6 M 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, cefepime 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 its elimination half-life, enhance nephrotoxicity, and increase the risk of nephrotoxicity. Concomitant use of cefepime and aminoglycosides increases the risk of ototoxic effects of the latter.

Effect on laboratory test results.

Cefepime administration may lead to false-positive glucose tests in urine 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 to medicinal products. If an allergic reaction occurs, administration of the drug must be discontinued. Severe hypersensitivity reactions may require the use of adrenaline, hydrocortisone, antihistamines, and other emergency measures.

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

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

Appropriate tests should be performed to identify the causative microorganism and determine its susceptibility to cefepime. Cefimek may be used as monotherapy prior to identification of the causative microorganism, as it has a broad spectrum of antibacterial activity against both gram-positive and gram-negative microorganisms. If there is a risk of mixed aerobic-anaerobic infection (including Bacteroides fragilis), treatment with cefepime in combination with an agent active against anaerobes may be initiated before the pathogen is identified.

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, this should be taken into account when prescribing the dose, and renal function must be monitored.

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

Prothrombin time should be monitored.

In patients with impaired renal function (creatinine clearance < 60 mL/min), the dose of the drug should be adjusted to compensate for slower renal elimination. Since prolonged serum antibiotic concentrations may occur at standard doses in patients with renal impairment or other conditions that may worsen kidney 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 Cefimek, 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 receiving doses exceeding the recommended dose, and in elderly patients with renal impairment receiving recommended doses of cefepime. Some cases have occurred in patients receiving doses adjusted according to their renal function. In most cases, symptoms of nephrotoxicity were reversible and resolved after discontinuation of cefepime and/or after hemodialysis.

The pharmacokinetics of cefepime in patients with hepatic dysfunction are not altered. Dose adjustment is not required for these patients.

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 treatment with Cefimek should be monitored. Mild forms of colitis may resolve spontaneously after completion of therapy; moderate or severe cases may require specific treatment.

The use of antibacterial agents alters the normal flora of the large intestine 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 the diagnosis of pseudomembranous colitis, appropriate therapeutic measures should be taken. Mild to moderate pseudomembranous colitis may resolve after discontinuation of the drug. In cases of moderate or severe colitis, administration of fluids and electrolytes, protein supplementation, and an antibacterial agent effective against Clostridium difficile should be considered.

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

Many cephalosporins, including cefepime, are associated with reduced prothrombin activity. Patients at risk include those with impaired liver or kidney function, malnourished patients, and those receiving prolonged courses of antimicrobial therapy. Prothrombin should be monitored in patients at risk, and vitamin K should be administered if necessary.

During treatment with Cefimek, positive results in the direct Coombs test may be obtained. When performing hematological or transfusion procedures involving the antiglobulin test for blood group determination by the cross-matching method, or during 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 the drug's administration.

When lidocaine is used as a solvent for Cefimek in children and adults, 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.

Animal studies have shown no effect on reproductive function and no harmful effects on the fetus. However, adequate and well-controlled studies in pregnant women have not been conducted; therefore, Cefimek should be prescribed during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

Cefepime passes into 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 effects affecting reaction speed occur, patients should refrain from driving or operating machinery.

Administration and Dosage

The drug is intended for parenteral administration. The dosage is determined individually by the 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 longer treatment. Dosing recommendations for cefepime in adults are provided in Table 2.

Table 2. Cefepime dosing recommendations for adults

with creatinine clearance >60 mL/min.

*Including cases associated with concomitant bacteremia.

** Or until resolution of neutropenia. For patients in whom fever resolves but neutropenia persists for more than 7 days, the need for continuation of antibacterial therapy should be reevaluated.

*** Intramuscular administration is indicated only for uncomplicated or complicated infections caused by E. coli of mild to moderate severity, when this route of administration is considered more appropriate.

Prophylaxis of infections during surgical procedures. 60 minutes prior to the start of surgery, administer 2 g of the drug intravenously over 30 minutes to adults. After completion of this infusion, an additional 500 mg of metronidazole should be administered intravenously. Metronidazole solutions must not be administered simultaneously with Cefimek. The infusion system should be flushed before administration of metronidazole.

During prolonged surgical procedures (exceeding 12 hours), a repeat dose of the same amount of cefepime is recommended 12 hours after the first dose, followed by administration of metronidazole.

Renal function impairment. Dose adjustment is required for patients with impaired renal function (creatinine clearance less than 30 mL/min). Recommended doses of cefepime for adults are shown in Table 3.

Table 3. Recommended doses of cefepime for adult patients
with impaired renal function

*On hemodialysis days, Cefimek should be administered as described in Table 3. If possible, Cefimek should be administered at the same time each day.

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

Men:

Creatinine clearance (mL/min) =

Women:

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

During a 3-hour hemodialysis session, approximately 68% of the administered dose is eliminated from the body. 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, every 48 hours.

Cefimek should be administered to children aged 1–2 months 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:

Creatinine clearance (mL/min/1.73 m²) =

or

Creatinine clearance (mL/min/1.73 m²) =

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 in children should not exceed the recommended adult dose. The usual recommended dose for 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 (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.

Cefimek should be administered to children weighing 40 kg or more in the same manner as in adults.

Administration of the drug. Cefimek can be administered intravenously or by deep intramuscular injection into a large muscle (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, Cefimek should be dissolved in sterile water for injection, 5% dextrose injection solution, or 0.9% sodium chloride injection solution, as specified in Table 4. Administer intravenously slowly over 3–5 minutes or via an intravenous infusion system.

Intramuscular administration. Cefimek 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 concentrations indicated in Table 4.

Table 4

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

Prepared 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. When lidocaine is used as a solvent, safety information regarding lidocaine should be taken into account. When prescribing the drug to children aged 1 month and older, the physician must carefully assess the dose depending on the patient's age, body weight, severity and type of infection, and renal function.

Overdose.

Symptoms: In case of a significant overdose, adverse reactions 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 disorders: hypersensitivity reactions, including anaphylaxis, anaphylactic shock, angioedema, rash, erythema, pruritus, urticaria, fever.

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

Hepatobiliary disorders: hepatitis, cholestatic jaundice, decreased prothrombin activity.

Nervous system disorders: dizziness, headache, restlessness, insomnia, paresthesia, confusion/loss of consciousness, seizures/epileptiform convulsions, 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 disorders: tachycardia, vasodilation, chest pain, peripheral edema.

Renal and urinary disorders: renal failure.

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

Laboratory abnormalities: 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; pseudopositive glucose in urine test.

In addition to the above-mentioned adverse reactions, other adverse reactions characteristic of 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 in bulk form).

Storage conditions.

Store in the original packaging, out of reach of children, at a temperature not exceeding 25 °C. Prepared solutions for intravenous and intramuscular administration may be stored for up to 24 hours at room temperature or for 7 days in a refrigerator (2–8)°C.

Incompatibility.

Do not mix with other medicinal products in the same container. Use only the solvents specified in the sections “Dosage and administration” and “Interaction with other medicinal products and other types of interactions”.

Packaging.

1 or 25 vials with powder in a cardboard box.

Prescription status.

Prescription only.

Manufacturer: LLC "AVANT" (packaging of the in bulk form produced by NSPC Hebei Huamin Pharmaceutical Company Limited, China).

Manufacturer's address and place of business.

Ukraine, 03057, Kyiv, Anton Tsydika St., 14.

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