Cefepime

Application of the medicinal product Cefepime

Composition:

Active substance: cefepime;

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

*Sterile mixture of cefepime hydrochloride and L-arginine.

Pharmaceutical form. Powder for solution for injection.

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

Pharmacotherapeutic group. Antimicrobial agents for systemic use. Other beta-lactam antibiotics. Fourth-generation cephalosporins. Cefepime.

ATC code J01D E01.

Pharmacological Properties.

Pharmacodynamics.

Cefepime inhibits the synthesis of enzymes involved in the bacterial cell wall and has a broad spectrum of activity against various Gram-positive and Gram-negative bacteria. Cefepime 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 – minimal inhibitory concentration 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. agglomeratus, 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); H. parainfluenzae; Hafnia alvei; Legionella spp.; Morganella morganii; Moraxella catarrhalis (Branhamella catarrhalis) (including β-lactamase-producing strains); Neisseria gonorrhoeae (including β-lactamase-producing strains); Neisseria 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.; B. melaninogenicus (within 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 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 individuals 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 into N-methylpyrrolidine N-oxide. The average total clearance is 120 mL/min. Cefepime is excreted almost exclusively via renal mechanisms—primarily by 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 N-oxide, and about 2.5 % as cefepime epimer. Plasma protein binding of cefepime is less than 19 % and is independent of drug concentration in serum.

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.

Studies conducted in patients with varying 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 impairment or cystic fibrosis. Dose adjustment in such patients is not required.

When administering cefepime at a dose of 50 mg/kg every 12 hours, no drug accumulation was observed, whereas at steady state, maximum plasma concentration, area under the curve, and elimination half-life increased by approximately 15 % when administered at 50 mg/kg 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;
• sepsis.

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

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

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

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

To avoid potential drug interactions with other agents, solutions of the medicinal product Cefepime (as with most other β-lactam antibiotics) should not be administered simultaneously with solutions of metronidazole, vancomycin, gentamicin, tobramycin sulfate, or netilmicin sulfate. If Cefepime is prescribed together with any of these agents, each antibiotic should be administered separately.

Effect on laboratory test results.

Cefepime administration may lead to false-positive glucose in urine tests when using Benedict's reagent. Enzymatic glucose tests based on glucose oxidase reaction are recommended.

Special precautions.

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

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, especially to medicinal products. If an allergic reaction occurs, administration of the drug should be discontinued. Severe immediate-type hypersensitivity reactions may require treatment with adrenaline and other therapeutic measures.

Use with caution in patients with gastrointestinal disorders (particularly in the medical history), especially colitis.

Cases of pseudomembranous colitis have been reported during treatment with nearly all broad-spectrum antibiotics. Therefore, it is important to consider the possibility of this condition in the event of diarrhea occurring during therapy with Cefepime. 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 initiated. Mild to moderate pseudomembranous colitis may resolve after discontinuation of the drug. In cases of moderate to severe colitis, consideration should be given to the need for fluid and electrolyte replacement, protein supplementation, and administration of an antibacterial agent effective against Clostridium difficile.

For patients with impaired renal function (creatinine clearance ≤ 60 mL/min), the dose of cefepime must be adjusted to compensate for reduced renal elimination. Because antibiotic exposure may increase when standard doses of cefepime are administered to patients with renal insufficiency or other conditions that may impair renal function, the maintenance dose of cefepime should be reduced in such patients. The next dose of cefepime should be determined based on the degree of renal impairment, severity of infection, and microbial susceptibility to the antibiotic. During post-marketing surveillance of cefepime products, severe adverse events, including life-threatening or fatal cases, have been reported: encephalopathy (disturbances of consciousness, including confusion, hallucinations, stupor, and coma), myoclonia, and seizures. Most cases occurred in patients with impaired renal function who received doses of cefepime exceeding the recommended levels. Occasionally, severe reactions 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.

Warnings.

It is unlikely that prescribing cefepime in the absence of proven or suspected bacterial infection or for prophylactic use (except for prevention of postoperative complications) will be beneficial; such use increases the risk of emergence of bacteria resistant to this medicinal product. Prolonged use of cefepime (as with other antibiotics) may lead to the development of superinfection. The patient's condition should be re-evaluated regularly. If superinfection develops, appropriate measures should be taken.

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

During treatment with cefepime, positive results in the direct Coombs test may occur. When performing hematological or transfusion procedures involving cross-matching with 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 drug administration.

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

When lidocaine is used as a solvent, safety information regarding lidocaine should be taken into account.

Use during pregnancy or breastfeeding.

Adequate and well-controlled studies 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 passes into breast milk in very small amounts; therefore, breastfeeding should be discontinued during treatment with Cefepime.

Ability to affect reaction speed when driving or operating machinery.

The effect of cefepime on the ability to drive or operate machinery has not been studied; however, it should be considered that adverse reactions affecting the nervous system may occur during treatment.

Dosage and Administration.

The usual dose for adults 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.

Dosage and route of administration vary depending on the sensitivity 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 prophylaxis of infections during surgical procedures. 2 g of the drug should be administered intravenously over 30 minutes, 60 minutes prior to the start of surgery. After completion, an additional 500 mg of metronidazole should be administered intravenously. Metronidazole solutions should not be administered simultaneously with the drug Cefepime. 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 should be administered 12 hours after the initial dose, followed by administration of metronidazole.

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

* On the day of dialysis, the injection must be administered after the dialysis session.

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

Men:

Women:

creatinine clearance (ml/min) = the 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 repeat dose equal to the initial dose should be administered. During continuous ambulatory peritoneal dialysis, the drug may be used at the initial standard recommended doses of 500 mg, 1 g, or 2 g, depending on the severity of infection, administered every 48 hours.

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 with body weight up to 40 kg receiving Cefepime therapy should be closely monitored.

Children aged 2 months and older. The maximum dose in children should not exceed the recommended adult dose. The usual recommended dose in children with body weight up to 40 kg for complicated or uncomplicated urinary tract infections (including pyelonephritis), uncomplicated skin infections, pneumonia, and for empirical treatment of febrile neutropenia is 50 mg/kg every 12 hours (every 8 hours in patients with febrile neutropenia and bacterial meningitis).

The usual duration of treatment is 7–10 days; severe infections may require longer therapy. Children with body weight of 40 kg and above should receive Cefepime as in adults.

In children with impaired renal function, dose reduction or increased dosing intervals are recommended.

Calculation of creatinine clearance in children:

or

Administration of the drug. Cefepime may be administered intravenously (from 3−5 minutes to 30 minutes) 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 injections, 5% glucose solution for injections, or 0.9% sodium chloride solution, as specified in the table below. Administer intravenously slowly over 3−5 minutes or via an intravenous infusion system.

Intramuscular administration. Cefepime may be reconstituted with sterile water for injections, 0.9% sodium chloride solution for injections, 5% glucose solution for injections, bacteriostatic water for injections 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 diluent, a skin test for tolerance should be performed prior to administration, and safety information regarding lidocaine must be taken into account.

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

Appropriate microbiological studies 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 due to its broad spectrum of antibacterial activity against both gram-positive and gram-negative microorganisms. In patients at risk of mixed aerobic/anaerobic (including Bacteroides fragilis) infections, treatment with cefepime may be initiated in combination with an agent active against anaerobes, pending identification of the causative pathogen.

Prepared solutions for intramuscular and intravenous injection are stable for 24 hours at room temperature or for 7 days if stored refrigerated (2−8 °C).

Children.

May be administered to children aged 1 month and older.

Overdose.

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

Treatment: 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.

Infections and infestations: vaginitis, oral candidiasis, vaginal candidiasis;

Central nervous system disorders: headache, dizziness, insomnia, paresthesia, restlessness, seizures, myoclonus, epileptiform seizures, altered state of consciousness, encephalopathy (loss of consciousness, hallucinations, stupor, coma);

Cardiovascular system disorders: vasodilation, chest pain, tachycardia, hemorrhage;

Gastrointestinal disorders: nausea, vomiting, diarrhea, abdominal pain, constipation, dyspepsia, colitis (including pseudomembranous colitis);

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

Renal and urinary system disorders: genital pruritus, renal failure, toxic nephropathy, renal dysfunction;

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

Skin and subcutaneous tissue disorders: pruritus, rash, urticaria, erythema, Stevens−Johnson syndrome, erythema multiforme, toxic epidermal necrolysis;

Blood and lymphatic system disorders: neutropenia, agranulocytosis, transient leukopenia, thrombocytopenia, aplastic anemia, hemolytic anemia, eosinophilia, pancytopenia, bleeding;

Hepatobiliary disorders: hepatitis, hepatic function abnormalities, cholestasis, cholestatic jaundice;

Administration site reactions: reactions at the site of administration, including phlebitis and inflammation with intravenous administration; pain and/or inflammation at the injection site with intramuscular administration;

Other: peripheral skin edema, altered taste sensation, asthenia, fever, sweating, back pain;

Laboratory test 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, decreased phosphorus levels, hypocalcemia (more common in elderly patients). There are no reports on clinical consequences of changes in calcium or phosphorus levels. Transient increases in blood urea nitrogen and/or serum creatinine; anemia, eosinophilia, agranulocytosis, transient thrombocytopenia, elevated calcium levels. Transient leukopenia and neutropenia, decreased hematocrit have also been observed.

Shelf life.

2 years.

Storage conditions.

Store in a light-protected place at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Incompatibilities.

Do not mix with other medicinal products in the same container.

Use only the solvents specified in the section "Administration and dosage".

Packaging.

500 mg or 1000 mg of the medicinal product in a glass vial stoppered with a rubber plug and sealed with an aluminum crimp cap fitted with a flip-off cap ensuring first-opening control.

1 vial per cardboard pack.

Prescription status. Prescription only.

Manufacturer.

Astral Steritech Private Limited
Astral steritech Private Limited

Manufacturer's address and location of its business operations.

911, G.I.D.C., Makarpura, Vadodara, Gujarat, 390 010, India
911, Gidc, Makarpura, Vadodara, Gujarat 390 010, India (IND)

Marketing authorization holder.

M. Biotech Ltd
M. Biotech ltd

Address of the marketing authorization holder.

Gladstone House, 77–79 High Street, Egham TW20 9HY, Surrey, United Kingdom
Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom