Quadrocef®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KVADROTSEF® (QUADROCEF)

Composition:

Active substance: cefepime;

1 vial contains cefepime (as cefepime hydrochloride monohydrate) 1 g;

Excipient: L-arginine.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white or pale yellow powder.

Pharmacotherapeutic group. Antibacterial agents for systemic use. Other β-lactam antibiotics. Fourth-generation cephalosporins. ATC code J01D E01.

Pharmacological Properties.

Pharmacodynamics.

Cefepime is a broad-spectrum, fourth-generation β-lactam cephalosporin antibiotic for parenteral administration. It exhibits bactericidal activity. It is active against both Gram-positive and Gram-negative bacteria, including most strains resistant to aminoglycosides or third-generation cephalosporin antibiotics such as ceftazidime. Cefepime is highly resistant to the effects of most β-lactamases and rapidly penetrates Gram-negative bacteria. The binding affinity of cefepime to penicillin-binding protein PBP 3 significantly exceeds that of other parenteral cephalosporins. The moderate affinity of cefepime to PBPs 1a and 1b also contributes to its level of bactericidal activity. The MBC (minimum bactericidal concentration)/MIC ratio for cefepime is less than 2 for more than 80% of isolates of all susceptible Gram-positive and Gram-negative bacteria.

Cefepime inhibits the synthesis of bacterial cell wall enzymes. The drug has low affinity for chromosomally encoded β-lactamases.

Cefepime is active against the following microorganisms:

Gram-positive aerobes: Staphylococcus aureus (including β-lactamase-producing strains) and Staphylococcus epidermidis (including β-lactamase-producing strains); other staphylococcal strains (including S. hominis, S. saprophyticus); Streptococcus pyogenes (group A); Streptococcus agalactiae (group B); Streptococcus pneumoniae (including strains with intermediate resistance to penicillin – MIC from 0.1 to 1 μg/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 cefepime and most other cephalosporin antibiotics);

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 (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 catarrhalis (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.

Cefepime is inactive against many strains of Xanthomonas (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.

Cefepime is completely absorbed after intramuscular administration.

Mean plasma concentrations of cefepime in healthy adult males at various time points after single intravenous and intramuscular administration are shown in Table 1.

Table 1.

Plasma concentrations of cefepime (μg/mL) following intravenous (i.v.) and intramuscular (i.m.) 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 and is independent of dose within the range of 250 mg to 2 g. No drug accumulation was observed with intravenous doses up to 2 g administered every 8 hours over 9 days.

Cefepime is metabolized to N-methylpyrrolidine, which is rapidly converted to N-methylpyrrolidine oxide. Cefepime is primarily eliminated by glomerular filtration (total cefepime clearance is approximately 120 mL/min, with mean hepatic clearance of 110 mL/min). Approximately 80–85% 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 the cefepime epimer. Plasma protein binding of cefepime is less than 19% and does not depend on drug concentration in serum.

Dose adjustment is not required in patients aged 65 years and older with normal renal function.

In patients with renal impairment, the elimination half-life of cefepime is prolonged, and there is a linear relationship between total drug clearance and creatinine clearance. The elimination half-life in patients with severe renal dysfunction requiring hemodialysis is 13 hours, and 19 hours in those undergoing continuous ambulatory peritoneal dialysis. Dose adjustment should be individualized in patients with abnormal renal function.

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

Children. Pharmacokinetic studies of cefepime have been conducted in children aged 2 months to 11 years after single or multiple doses administered every 8 or every 12 hours. After a single intravenous injection, the mean total body clearance and steady-state volume of distribution were 3.3 (1.0) mL/min/kg and 0.3 (0.1) L/kg, respectively. Renal excretion of unchanged cefepime was 60.4 (30.4)% of the administered dose, and mean renal clearance was 2 (1.1) mL/min/kg. Patient age and sex did not significantly affect total body clearance or volume of distribution when corrected for body weight. No drug accumulation was observed with cefepime dosing at 50 mg/kg every 12 hours, whereas with dosing at 50 mg/kg every 8 hours, maximum plasma concentration, area under the curve, and elimination half-life increased by approximately 15% at steady state. Cefepime exposure in children after intravenous administration of 50 mg/kg is comparable to that observed in adults after intravenous administration of 2 g. After intravenous administration, the mean peak plasma concentration of cefepime at steady state was 68 mcg/mL, reached within 0.75 hours. Eight hours after intramuscular administration, the mean plasma concentration of cefepime was 6 mcg/mL. The absolute bioavailability of cefepime after intramuscular injection averaged 82%.

Due to the inability to identify the causative pathogen and determine its antibiotic susceptibility, or due to time constraints, cefepime may be used empirically because of its broad-spectrum antibacterial activity. In patients at risk for mixed aerobic-anaerobic infections, treatment with cefepime may be initiated before pathogen identification, in combination with an anti-anaerobic agent.

Clinical characteristics.

Indications.

Adults.

Infections caused by microorganisms sensitive to the drug:

• respiratory tract infections, including pneumonia, bronchitis;
• skin and subcutaneous 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 subcutaneous 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, or other β-lactam antibiotics.

Interaction with other medicinal products and other forms of interaction.

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 reported following 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 M 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, solutions of Quadrocef® (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 Quadrocef® with these agents is necessary, each antibiotic should be administered separately.

Effect on laboratory test results.

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

Special precautions for use.

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

It is essential to determine precisely whether the patient has previously experienced immediate-type hypersensitivity reactions to cefepime or other β-lactam antibiotics. Antibiotics should be administered cautiously to all patients with any form of allergy, particularly drug allergies. If an allergic reaction occurs, the drug must 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 in the history), especially colitis.

Cases of pseudomembranous colitis have been reported with the use of almost all broad-spectrum antibiotics. Therefore, the possibility of this condition should be considered if diarrhea develops during treatment with Quadrocef®. 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. Cases of mild to moderate pseudomembranous colitis may resolve after discontinuation of the drug. In moderate to severe cases, consideration should be given to fluid and electrolyte replacement, protein supplementation, and administration of an antibacterial agent effective against Clostridium difficile.

In patients with impaired renal function (creatinine clearance ≤ 60 mL/min), the dose of cefepime must be adjusted to compensate for reduced renal elimination. Because prolonged serum antibiotic concentrations may occur when standard doses of cefepime are administered to patients with renal impairment or other conditions that may impair renal function, the maintenance dose of cefepime should be reduced in such patients. The degree of renal impairment, severity of infection, and microbial susceptibility to the antibiotic should be taken into account when determining the subsequent dose of cefepime. During post-marketing surveillance of cefepime-containing drugs, severe, life-threatening, or fatal adverse events have been reported, including encephalopathy (altered mental status, including confusion, hallucinations, stupor, and coma), myoclonus, and seizures. Most cases occurred in patients with impaired renal function who received doses exceeding the recommended dosage. Some cases occurred in patients receiving doses adjusted according to renal function. In most cases, symptoms of neurotoxicity were reversible and resolved after discontinuation of cefepime and/or hemodialysis.

Precautions.

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

Many cephalosporins, including cefepime, are associated with reduced prothrombin activity. At-risk patients include those with hepatic or renal dysfunction, those with poor nutrition, and those receiving prolonged courses of antimicrobial therapy. Prothrombin levels should be monitored in at-risk patients, 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 blood group determination by cross-matching, 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 result from 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.

Use during pregnancy or breastfeeding.

Cefepime may be prescribed during pregnancy only when the expected benefit to the mother outweighs the potential risk to the fetus.

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

Ability to affect reaction speed when driving or operating machinery.

The effect of cefepime on reaction speed during driving or operating machinery has not been studied; however, it should be considered that adverse reactions affecting the nervous system may occur during treatment.

Method of administration and dosage.

The usual dosage 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.

However, dosage and route of administration vary depending on the susceptibility of the causative microorganisms, severity of the infection, and the patient's renal function. Dosage recommendations for Quadrocef® in adults are provided in Table 2.

When using lidocaine solution as a solvent for intramuscular administration of the drug, safety information regarding lidocaine should be taken into account, and a skin test for tolerance to lidocaine must be performed.

Table 2.

Dosage of Quadrocef® for adults

For 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 of administration, additionally administer 500 mg of metronidazole intravenously. Metronidazole solutions should not be administered simultaneously with Quadrocef®. The infusion system should be flushed before administration of metronidazole.

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

Renal function impairment. Dose adjustment of Quadrocef® is required in patients with impaired renal function (creatinine clearance less than 30 mL/min).

Table 3.

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 eliminated from the body over 3 hours. A supplemental dose equal to the initial dose should be administered after each dialysis session. For continuous ambulatory peritoneal dialysis (CAPD), 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.

For 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)

Infants aged 1 to 2 months. Quadrocef® 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 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 for patients with febrile neutropenia and bacterial meningitis). The usual duration of treatment is 7–10 days; severe infections may require longer treatment.

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

Administration of the drug. Quadrocef® 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, Quadrocef® should be dissolved in sterile water for injection, 5% dextrose solution for injection, or 0.9% sodium chloride solution for injection, as specified in Table 4. It should be administered intravenously slowly over 3–5 minutes or via an intravenous infusion system.

Intramuscular administration. Quadrocef® can be dissolved in sterile water for injection, 0.9% sodium chloride solution for injection, 5% dextrose solution for injection, bacteriostatic water for injection with parabens or benzyl alcohol, or 0.5% or 1% lidocaine hydrochloride solution, at concentrations indicated in Table 4. When lidocaine is used as a solvent, a skin sensitivity test should be performed before administration.

Table 4

Cefepime concentrations after dilution

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 its (their) sensitivity to cefepime. However, Quadrocef® may be used as monotherapy prior to identification of the causative microorganism, since the drug has a 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 Quadrocef® may be initiated in combination with an agent active against anaerobes, prior to identification of the causative organism.

Children. The drug may be administered to children aged 1 month and older.

Overdose.

Symptoms: In cases of significant overdose, particularly in patients with impaired renal function, adverse effects may intensify. 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 the 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, angioneurotic edema;

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

Cardiovascular system disorders: tachycardia, vasodilation;

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

Nervous system disorders: headache, insomnia, restlessness, seizures, dizziness, paresthesia, epileptiform seizures, encephalopathies (loss of consciousness, hallucinations, stupor, coma), myoclonia;

Hepatobiliary disorders: hepatitis, cholestatic jaundice;

Skin and subcutaneous tissue disorders: rash, pruritus, urticaria;

Other reactions: asthenia, sweating, fever, vaginitis, erythema, chest pain, back pain, peripheral edema, genital pruritus, candidiasis, renal failure.

Local reactions at the site of administration:

Intravenous administration: phlebitis and inflammation;

Intramuscular administration: pain, inflammation.

Laboratory findings: increased levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin; anemia, eosinophilia, prolonged prothrombin time or activated partial thromboplastin time (APTT), and a positive Coombs test without hemolysis. Transient increases in blood urea nitrogen and/or serum creatinine, transient leukopenia, neutropenia, agranulocytosis, transient thrombocytopenia.

Possible adverse reactions characteristic of cephalosporin antibiotics: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, toxic nephropathy, aplastic anemia, hemolytic anemia, bleeding, hepatic dysfunction, cholestasis, pancytopenia.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

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 g in a vial, 1 vial per pack.

Prescription status. Prescription only.

Manufacturer. JSC "Kyivmedpreparat".

Manufacturer's address.
139 Saksaganskogo Street, Kyiv, 01032, Ukraine.