Cefotrin

Instructions for Medical Use of the Medicinal Product CEFOTRINE (CEFOTRINE)

Composition:

Active substance: cefepime hydrochloride USP equivalent to cefepime;

1 vial contains cefepime hydrochloride USP equivalent to cefepime − 1 g;

Excipient: L-arginine.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white to light yellow powder.

Pharmacotherapeutic group.

Antibacterial agents for systemic use. Beta-lactam antibiotics. Fourth-generation cephalosporins. ATC code J01D E01.

Pharmacological properties.

Pharmacodynamics.

Cefepime inhibits the synthesis of bacterial cell wall enzymes 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 — 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 (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); N. 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., 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.

Mean plasma concentrations of cefepime in healthy adult males at various time points after single intravenous and intramuscular administration are presented in the table below.

Mean plasma concentrations of cefepime (μg/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 volunteers who received 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 to N-methylpyrrolidine oxide. The mean total clearance is 120 mL/min. Cefepime is eliminated almost exclusively via renal mechanisms, primarily through glomerular filtration (mean renal clearance is 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 oxide, and about 2.5% as the cefepime epimer. Plasma protein binding of cefepime is less than 19% and is independent of drug concentration in serum.

Dose adjustment is not required in patients aged 65 years and older with normal renal function, despite their lower renal clearance compared to younger patients.

Studies conducted in patients with various degrees of renal impairment have demonstrated an increased elimination half-life. On average, the half-life in patients with severe renal dysfunction requiring dialysis is 13 hours during hemodialysis and 19 hours during peritoneal dialysis.

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

Clinical characteristics.

Indications.

Adults.

Infections caused by microorganisms sensitive to the drug:

• respiratory tract infections, including pneumonia, bronchitis;
• skin, subcutaneous tissue, 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 subcutaneous 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 types of interactions.

When high doses of aminoglycosides are administered concomitantly with Cefotrin, renal function should be closely monitored due to the potential nephrotoxicity and ototoxicity of aminoglycoside antibiotics. Nephrotoxicity has been observed after 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 solution; 5% and 10% glucose injection solutions; 6M sodium lactate injection solution; 5% glucose and 0.9% sodium chloride injection solution; Ringer's lactate solution with 5% glucose injection solution.

To avoid potential drug interactions with other medicinal products, cefepime solutions (like most other β-lactam antibiotics) should not be administered simultaneously with metronidazole, vancomycin, gentamicin, tobramycin sulfate, or netilmicin sulfate solutions. If Cefotrin is prescribed together with these agents, 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 enzymatic glucose oxidation reactions.

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 hematologic disorders with progressive severe neutropenia), monotherapy may be insufficient and combination antimicrobial therapy is indicated.

It is essential to determine 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, particularly drug allergies. If an allergic reaction occurs, the drug should be discontinued. Severe immediate-type hypersensitivity reactions may require administration of epinephrine and other therapeutic interventions.

Cases of pseudomembranous colitis have been reported with the use of nearly all broad-spectrum antibiotics. Therefore, the possibility of this condition should be considered in any patient who develops diarrhea during treatment with Cefotrin. Pseudomembranous colitis may range from mild diarrhea to fatal colitis. Mild cases of colitis may resolve after discontinuation of the drug; moderate or severe cases may require specific treatment.

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

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

In patients with impaired renal function (creatinine clearance < 60 mL/min), the dose of cefepime should be adjusted to compensate for reduced renal elimination. Since prolonged antibiotic serum concentrations may occur at standard doses in patients with renal impairment or other conditions that may impair renal function, the maintenance dose should be reduced when administering cefepime to such patients. The degree of renal impairment, severity of infection, and susceptibility of the causative organisms should be taken into account when determining the subsequent dose.

When using cefepime, as with other drugs in this class, serious adverse reactions such as reversible encephalopathy (confusion, including altered 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 occurred in patients receiving doses adjusted according to renal function. In most cases, symptoms of nephrotoxicity were reversible and resolved after discontinuation of cefepime and/or hemodialysis.

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

Antibacterial agents may alter the normal gut flora of the colon and promote overgrowth of Clostridium species. Studies indicate that the toxin produced by Clostridium difficile is the primary cause of antibiotic-associated colitis. Once pseudomembranous colitis is diagnosed, 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 fluid and electrolyte replacement, protein supplementation, and administration of an antibacterial agent effective against Clostridium difficile.

Warnings.

It is unlikely that prescribing cefepime in the absence of proven or suspected bacterial infection or for prophylactic use will be beneficial, but such use may increase the risk of developing bacteria resistant to this drug. Prolonged use of cefepime (as with other antibiotics) may lead to superinfection. The patient's condition should be reassessed 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 hepatic or renal 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 cefepime therapy, positive results in the direct Coombs test may be observed. When performing hematological or transfusion procedures, including blood group determination by cross-matching, when performing the antiglobulin test, or during Coombs testing in newborns whose mothers received cephalosporin antibiotics before delivery, it should be noted that a positive Coombs test may be due to drug administration.

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

L-arginine has been shown to alter glucose metabolism and simultaneously increase serum potassium levels when administered at doses 33 times higher than the maximum recommended dose of cefepime. Effects at lower doses are currently unknown.

Disposal.

Environmental release of the medicinal product should be minimized. Measures should be taken to prevent the entry of the medicinal product into sewage systems or household waste.

Use during pregnancy or breastfeeding.

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

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

Ability to affect reaction speed when driving or operating machinery.

Given the potential effect of the drug on the central nervous system, it is recommended to refrain from driving or operating machinery during treatment with Cefotrin.

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 may vary depending on the susceptibility of the causative microorganisms, the severity of the infection, and the patient's renal function.

Dosage recommendations for the drug Cefotrin in adults are provided in the table.

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 that, additionally administer 500 mg of metronidazole intravenously. Metronidazole solutions should not be administered simultaneously with the drug Cefotrin. The infusion system should be flushed before administration of metronidazole.

During prolonged (over 12 hours) surgical procedures, 12 hours after the first dose, re-administration of the same dose of Cefotrin is recommended, followed by administration of metronidazole.

Renal function impairment. In patients with impaired renal function (creatinine clearance less than 30 ml/min), the dose of Cefotrin must be adjusted.

Recommended doses of cefepime for adults

If only the serum creatinine concentration is known, creatinine clearance can be calculated using the formula 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 hemodialysis, approximately 68% of the drug dose is removed from the body over 3 hours. After each dialysis session, a repeat dose equal to the initial dose should be administered. For continuous ambulatory peritoneal dialysis (CAPD), the drug can be used at the normal recommended initial doses of 500 mg, 1 g, or 2 g, depending on the severity of infection, with a dosing interval of 48 hours.

Infants aged 1 to 2 months. 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 weighing less than 40 kg who are receiving Cefotrin therapy should be closely monitored.

In pediatric patients with impaired renal function, a reduction in dose or an increase in the dosing interval is recommended.

Calculation of creatinine clearance in children:

0.55 × height (cm)

creatinine clearance (mL/min/1.73 m²) = ---------------------------------

serum creatinine (mg/dL)

or

0.52 × height (cm)

creatinine clearance (mL/min/1.73 m²) = ------------------------------------------ − 3.6

serum creatinine (mg/dL)

Children aged 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 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 or bacterial meningitis). The usual duration of treatment is 7–10 days; severe infections may require longer treatment.

Children weighing 40 kg or more should receive Cefotrin as adults.

Administration of the drug. Cefotrin can be administered intravenously or by deep intramuscular injection into a large muscle mass (e.g., the upper outer quadrant of the gluteus maximus).

Intravenous administration. The intravenous route is preferred for patients with severe or life-threatening infections.

For intravenous administration, Cefotrin should be dissolved in sterile water for injection, 5% dextrose injection solution, or 0.9% sodium chloride injection solution, as indicated in the table below. It should be administered intravenously slowly over 3–5 minutes or via an intravenous infusion system.

Intramuscular administration. Cefotrin can be dissolved in sterile water for injection, 0.9% sodium chloride injection solution, 5% dextrose injection solution, bacteriostatic water for injection with parabens or benzyl alcohol, or 0.5% or 1% lidocaine hydrochloride solution, at the concentrations specified in the table below.

When lidocaine is used as a solvent, a skin test for tolerance should be performed before administration.

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 their susceptibility to cefepime. However, Cefotrin can be used as monotherapy prior to identification of the causative microorganism, since it has a 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 with Cefotrin can be initiated before identification of the causative agent, either as monotherapy or in combination with an agent active against anaerobes.

Children.

Can 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 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 prompt administration of epinephrine 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, taste alteration, diarrhea, colitis (including pseudomembranous colitis), abdominal pain, constipation;

Nervous system disorders: headache, insomnia, restlessness, convulsions, dizziness, paresthesia, epileptiform seizures;

Hepatobiliary system disorders: hepatitis, cholestatic jaundice;

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

Reproductive system disorders: genital pruritus, candidiasis;

Other adverse reactions: asthenia, sweating, fever, vaginitis, erythema, chest pain, back pain, peripheral edema.

Local reactions at the site of administration:

Intravenous administration – phlebitis and inflammation;

Intramuscular administration – pain, inflammation.

Post-marketing surveillance:

• Encephalopathy (loss of consciousness, hallucinations, stupor, coma), epileptiform seizures, myoclonia, renal failure;
• Anaphylaxis, including anaphylactic shock, transient leukopenia, neutropenia, agranulocytosis, and thrombocytopenia.

Laboratory findings: increased levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, anemia, eosinophilia, prolonged prothrombin time or partial thromboplastin time (PTT), and positive Coombs test without hemolysis. Transient increases in blood urea nitrogen and/or serum creatinine, as well as transient thrombocytopenia, were observed in less than 0.5% of patients. Transient leukopenia and neutropenia were also reported.

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.

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 vial with powder in a cardboard box.

Prescription status

Prescription only.

Manufacturer

Ananta Medicare Limited.

Manufacturer's address and location of operations

Chak 17 ML, Agro Food Park Road, RIICO Industrial Area, Udaipurwati, Sri Ganganagar-335002 (Rajasthan), India.

Marketing Authorization Holder

Ananta Medicare Ltd.

Address of the Marketing Authorization Holder and/or its representative

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.