Ukpim-1000

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT UKPIME-1000 (UKPIME-1000)

Composition:

Active substance: cefepime;

1 vial contains cefepime hydrochloride equivalent to cefepime 1000 mg;

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. Other β-lactam antibiotics. Fourth-generation cephalosporins. Cefepime. ATC code J01DE01.

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 both Gram-positive and Gram-negative bacteria, including most strains resistant to aminoglycosides or third-generation cephalosporins such as ceftazidime. Cefepime is highly stable against the action 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. Moderate affinity of cefepime for PBP 1a and 1b also contributes to its level of bactericidal activity. The MBC (minimum bactericidal concentration)/MIC (minimum inhibitory concentration) 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 penicillin resistance—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 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. 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.

Plasma concentrations of cefepime (µg/mL) following intravenous (i.v.) and intramuscular (i.m.) administration

Table 1

Therapeutic concentrations of cefepime are also achieved in urine, bile, peritoneal fluid, bronchial mucous secretion, 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 after intravenous administration of doses up to 2 g every 8 hours over 9 days.

Cefepime is metabolized to N-methylpyrrolidine, which is rapidly converted to N-methylpyrrolidine oxide. Cefepime is primarily eliminated via 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, approximately 6.8% as N-methylpyrrolidine oxide, and approximately 2.5% as the cefepime epimer. Plasma protein binding of cefepime is less than 19% and does not depend on drug concentration in serum.

In patients aged 65 years and older with normal renal function, dosage adjustment is not required.

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 patients undergoing continuous ambulatory peritoneal dialysis. In patients with abnormal renal function, the dose should be individually adjusted.

The pharmacokinetics of cefepime are not altered in patients with hepatic impairment or cystic fibrosis. Dosage adjustment is not required for these 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 influence total body clearance or volume of distribution when corrected for individual body weight. When cefepime was administered at a dose of 50 mg/kg every 12 hours, no drug accumulation was observed. However, with administration every 8 hours at 50 mg/kg, 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 at steady state was 68 µg/mL, reached within 0.75 hours. Eight hours after intramuscular injection, the mean plasma concentration of cefepime was 6 µg/mL. The absolute bioavailability of cefepime after intramuscular injection averaged 82%.

Due to the inability to identify the causative infectious agent and determine its antibiotic susceptibility, or due to lack of time, cefepime may be used for empirical therapy, as it has a broad spectrum of antibacterial activity. In patients at risk of mixed aerobic-anaerobic infection, 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 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 cephalosporin antibiotics, penicillins, or other β-lactam antibiotics.

Interaction with other medicinal products and other types of interactions.

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 after concomitant use 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% dextrose injection; 6 M sodium lactate injection; 5% dextrose and 0.9% sodium chloride injection; Ringer's lactate and 5% dextrose injection.

To avoid potential drug interactions with other medicinal products, solutions of Ukpim-1000 (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 Ukpim-1000 with these medicinal products 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. It is recommended to use glucose tests based on the enzymatic glucose oxidation reaction.

Special precautions.

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

It is necessary to clarify whether the patient has previously experienced immediate-type hypersensitivity reactions to cefepime or other β-lactam antibiotics. Antibiotics should be prescribed 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 immediate-type hypersensitivity reactions may require administration of epinephrine and other therapeutic interventions.

Use with caution in patients with gastrointestinal disorders (particularly in those with a history of 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 treatment. 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 cases of moderate or severe colitis, replacement of fluids and electrolytes, protein supplementation, and administration of an antibacterial agent effective against Clostridium difficile should be considered.

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 next 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), myoclonia, and seizures. Most cases occurred in patients with impaired renal function who received cefepime doses exceeding the recommended doses. 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.

Warnings.

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 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 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, malnourished patients, and those receiving prolonged courses of antimicrobial therapy. Prothrombin levels should be monitored in patients at risk, and vitamin K should be administered if necessary.

Positive results in the direct Coombs' test may occur during cefepime therapy. When performing hematological or transfusion procedures, including blood grouping by cross-matching, when performing the antiglobulin test or 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 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 still unknown.

Use during pregnancy or breastfeeding.

The drug may be prescribed during pregnancy only when 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.

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

Administration and dosage.

The usual dosage for adults is 1000 mg, 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 may vary depending on the sensitivity of the causative microorganisms, the severity of the infection, and the patient's renal function. Dosage recommendations for the drug in adults are provided in Table 2.

Table 2

For prevention of infections during surgical procedures. Adults should receive 2 g of the drug 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 solution should not be administered simultaneously with cefepime. The infusion system must be flushed before administration of metronidazole.

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

Renal function impairment. Cefepime is eliminated by the kidneys via glomerular filtration; therefore, dosage adjustment is required in patients with impaired renal function (creatinine clearance less than 30 mL/min) (Table 3).

Recommended doses of cefepime for adult patients

Table 3

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

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

Men:

body weight (kg) × (140 − age)

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

72 × serum creatinine (mg/dL)

Women:

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

During 3-hour hemodialysis, approximately 68% of the drug dose is removed from the body. After each dialysis session, a repeat dose equal to the initial dose must be administered. For continuous ambulatory peritoneal dialysis, the drug can be used at the initial usual recommended doses of 500 mg, 1 g, or 2 g, depending on the severity of infection, with a 48-hour interval between doses.

Children aged 1 to 2 months. The drug should be administered only for life-threatening indications at a dose calculated as 30 mg/kg body weight every 12 or 8 hours, depending on the severity of infection. Children weighing less than 40 kg receiving cefepime therapy must be closely monitored.

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 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 doses recommended for adults.

For 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)

The drug can be administered by deep intramuscular injection (0.5 g and 1 g), slow intravenous injection, or infusion (over 3–5 to 30 minutes).

Intravenous administration. Cefepime should be dissolved in water for injection or any other compatible diluent at concentrations specified in Table 3. Solutions for intravenous administration may be administered directly into the vein by slow (3–5 minutes) injection via an intravenous line or directly into a compatible infusion solution (administered over 30 minutes).

For intravenous administration, cefepime is compatible with the following diluents: water for injection, 0.9% sodium chloride injection (with or without 5% dextrose); 5% and 10% dextrose injection; 1/6 M sodium lactate injection; lactated Ringer's solution (with or without 5% dextrose).

Intramuscular administration. The drug can be dissolved in water for injection, 0.9% sodium chloride injection, 5% dextrose injection, bacteriostatic water for injection with parabens or benzyl alcohol, or 0.5% or 1% lidocaine hydrochloride solution, at concentrations specified in Table 4.

Table 4

The prepared solution should be stored for up to 24 hours at a temperature not exceeding 30 °C or for up to 7 days at 2–8 °C.

As with other parenterally administered medicinal products, the 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 determine susceptibility to cefepime. However, the drug 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 infection (including Bacteroides fragilis), treatment may be initiated in combination with an agent active against anaerobes, pending 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, especially in patients with impaired renal function, adverse effects may be intensified. Symptoms of overdose include encephalopathy accompanied by hallucinations, disturbances of 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, angioedema.

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, encephalopathy (loss of consciousness, hallucinations, stupor, coma), myoclonus.

Hepatobiliary system disorders: hepatitis, cholestatic jaundice.

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

Other: asthenia, increased 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 (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin; anemia, eosinophilia, prolonged prothrombin time or partial thromboplastin time, and positive Coombs test without hemolysis. Transient increases in blood urea nitrogen and/or serum creatinine, transient leukopenia, neutropenia, agranulocytosis, transient thrombocytopenia.

Possible adverse reactions typical for cephalosporin antibiotics: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhages, liver function disorders, cholestasis, pancytopenia.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging.

Keep out of reach and sight of children.

Incompatibility.

The medicinal product must not be mixed in the same container with other medicinal products except for the solvents specified in the section "Method of administration and dosage".

Packaging.

1 vial of powder in a cardboard package.

Prescription status.

Prescription only.

Manufacturer.

Sens Laboratory Pvt. Ltd.

Manufacturer's address and place of business.

VI/51B, P.O. Box No. 2, Kozhuvanal, Pala, Kottayam – 686 573, Kerala, India.