Cefepime ananta

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEFEPIME ANANTA (CEFEPIME ANANTA)

Composition:

Active substance: cefepime;

1 vial contains cefepime hydrochloride equivalent to cefepime 1 g or 2 g;

Excipient: L-arginine.

Pharmaceutical form. Powder for solution for injection.

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

Pharmacotherapeutic group.

Antibacterial agents for systemic use. Other β-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, minimal inhibitory concentration (MIC) ranging 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, such as 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 shown in Table 1.

Table 1

Mean plasma concentrations of cefepime (mcg/mL)

Cefepime dose	0.5 hour	1 hour	2 hours	4 hours	8 hours	12 hours
Intravenous
1 g	78.7	44.5	24.3	10.5	2.4	0.6
2 g	163.1	85.8	44.8	19.2	3.9	1.1
Intramuscular
1 g	14.8	25.9	26.3	16.0	4.5	1.4
2 g	36.1	49.9	51.3	31.5	8.7	2.3

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. 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 into N-methylpyrrolidine oxide. The average total clearance is 120 mL/min. Cefepime is eliminated 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, approximately 6.8% as N-methylpyrrolidine oxide, and approximately 2.5% as cefepime epimer. Protein binding of cefepime to plasma proteins is less than 19% and does not depend on drug concentration in serum.

Dose adjustment of Cefepime Ananta is not required in patients aged 65 years and older with normal renal function, despite 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 in patients with hepatic impairment or cystic fibrosis is not altered. Dose adjustment in such patients is not required.

Drug dosage – 50 mg/kg body weight administered intravenously over 5 to 20 minutes every 8 hours.

Children

In children aged 2 months to 11 years, following a single intravenous injection, the average steady-state total clearance and volume of distribution are 3.3 (±1.0) mL/min/kg and 0.3 (±0.1) L/kg, respectively.

Approximately 60.4 (±30.4)% of the administered cefepime dose is excreted unchanged in urine, with renal clearance averaging 2.0 (±1.1) mL/min/kg. After intramuscular administration, the average peak plasma concentration of cefepime at steady state is 68 mcg/mL, reached after 0.75 hours. Eight hours after intramuscular injection, the plasma concentration of cefepime is 6 mcg/mL. The absolute bioavailability following intramuscular injection of cefepime averages 82%. Patient age and sex do not influence drug clearance.

Table 2

Cefepime concentrations in cerebrospinal fluid (CSF) and plasma in children with bacterial meningitis

Time after administration (h)	Concentration in blood plasma (μg/mL)*	Concentration in CSF (μg/mL)*	CSF/blood plasma concentration ratio*
0.5	67.7 ± 51.2	5.7 ± 0.14	0.12 ± 0.14
1	44.1 ± 7.8	4.3 ± 1.5	0.10 ± 0.04
2	23.9 ± 12.9	3.6 ± 2.0	0.17 ± 0.09
4	11.7 ± 15.7	4.2 ± 1.1	0.87 ± 0.56
8	4.9 ± 5.9	3.3 ± 2.8	1.02 ± 0.64

* Age from 3.1 months to 12 years with a standard deviation in age of ± 3 years.

Drug dosage 50 mg/kg body weight administered intravenously over 5–20 minutes every 8 hours. Plasma concentration and CSF levels were determined at the end of infusion on day 2 or 3 of treatment with the drug.

Clinical characteristics.

Indications.

Adults

Infections caused by microorganisms sensitive to the drug:

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

Contraindications.

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

Special safety precautions.

The release of the medicinal product into the external environment should be minimized. Avoid contamination of sewage systems or household waste with the medicinal product.

Interaction with other medicinal products and other types of interactions.

When high doses of aminoglycosides are used concomitantly with cefepime, 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; 6 M sodium lactate injection solution; 5% glucose and 0.9% sodium chloride injection solution; Ringer's lactate with 5% glucose injection solution.

To avoid potential drug interactions with other agents, cefepime solutions (like most other β-lactam antibiotics) should not be administered simultaneously with solutions of metronidazole, vancomycin, gentamicin, tobramycin sulfate, or netilmicin sulfate. When cefepime is prescribed together with these agents, each antibiotic should be administered separately.

Effect on laboratory test results

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

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 severe progressive neutropenia), 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, cephalosporins, penicillins, or other β-lactam antibiotics. Antibiotics should be administered with caution to all patients with any type of allergy, particularly drug allergies. If an allergic reaction occurs, the drug must be discontinued immediately. Severe immediate-type hypersensitivity reactions may require administration of epinephrine and implementation of other therapeutic measures.

This medicinal product should be used with caution in patients with gastrointestinal disorders (particularly those with a history of gastrointestinal disease), especially colitis.

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

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 if diarrhea develops during cefepime therapy. Pseudomembranous colitis may range from mild diarrhea to fatal colitis. Studies indicate that the toxin produced by Clostridium difficile is the primary cause of antibiotic-associated colitis. Once pseudomembranous colitis is confirmed, appropriate therapeutic measures should be initiated. Mild cases of 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 worsen 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, life-threatening, or fatal adverse reactions 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 cefepime doses exceeding the recommended levels. 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.

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

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 developing bacteria resistant to this medicinal product. Prolonged use of cefepime (as with other antibiotics) may lead to superinfection. The patient's condition should be reassessed 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 hepatic or renal function, those with poor nutrition, 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.

Since the drug contains L-arginine in its formulation, it is also contraindicated in patients with hypersensitivity to L-arginine and in patients with acidosis. Therefore, the drug should be used with caution in patients with hyperkalemia.

During cefepime therapy, positive results in the direct Coombs test may be obtained. 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 considered that a positive Coombs test may be due to the use of the drug.

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.

Adequate and well-controlled studies in pregnant women have not been conducted; therefore, cefepime should be administered 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; therefore, breastfeeding should be discontinued during treatment with this drug.

Ability to affect reaction speed when driving or operating machinery.

Since adverse reactions affecting the central nervous system may occur during treatment, patients should refrain from driving or operating machinery.

Dosage and Administration

The usual dose for adults is 1 g, which should be 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 in adults are presented in Table 3.

Table 3

Severity of infection	Dose and route of administration	Frequency
Mild to moderate urinary tract infections	500 mg – 1 g intravenously or intramuscularly	every 12 hours
Other mild to moderate infections	1 g intravenously or intramuscularly	every 12 hours
Severe infections	2 g intravenously	every 12 hours
Very severe and life-threatening infections	2 g intravenously	every 8 hours

Prevention of infections during surgical procedures. Administer 2 g of the drug intravenously over 30 minutes, 60 minutes before the start of surgery in adults. After that, additionally administer 500 mg of metronidazole intravenously. Metronidazole solutions should not be administered simultaneously with cefepime. The infusion system must be flushed before administration of metronidazole.

During prolonged surgical procedures (over 12 hours), repeat administration of an equal dose of the drug is recommended 12 hours after the first dose, followed by administration of metronidazole.

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

Table 4

Recommended doses of cefepime for adults

Creatinine clearance (ml/min)	Recommended doses
> 50	Standard dosage appropriate to the severity of infection (see Table 3); dose adjustment not required
	2 g every 8 hours	2 g every 12 hours	1 g every 12 hours	500 mg every 12 hours
30–50	Dose adjustment according to creatinine clearance
	2 g every 12 hours	2 g every 24 hours	1 g every 24 hours	500 mg every 24 hours
11–29	2 g every 24 hours	1 g every 24 hours	500 mg every 24 hours	500 mg every 24 hours
≤10	1 g every 24 hours	500 mg every 24 hours	250 mg every 24 hours	250 mg every 24 hours
Hemodialysis	500 mg every 24 hours	500 mg every 24 hours	500 mg every 24 hours	500 mg every 24 hours

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 eliminated from the body over 3 hours. After each dialysis session, a supplemental dose equal to the initial dose should be administered. For continuous ambulatory peritoneal dialysis, 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, with a dosing interval of 48 hours.

For children aged 1–2 months, the drug should be prescribed only for life-threatening indications. The condition of children weighing less than 40 kg receiving cefepime should be closely monitored.

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)

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 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 (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.

For children weighing 40 kg or more, cefepime should be administered as in adults.

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

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 injection, 5% dextrose injection solution, or 0.9% sodium chloride injection solution, as specified in Table 5. Administer intravenously slowly over 3–5 minutes or via an intravenous infusion system.

Intramuscular administration. The drug 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 Table 5.

Table 5

Route of administration	Volume of solvent for dilution (ml)	Approximate volume of resulting solution (ml)
Intravenous administration: 1 g/vial	10	11.4
Intramuscular administration: 1 g/vial	3	4.4

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 studies should be performed to identify the causative microorganism(s) and to determine their susceptibility to cefepime. However, cefepime may be used as monotherapy before 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 in combination with an agent active against anaerobes may be initiated prior to pathogen identification.

Children.

The drug is indicated for use in children aged 1 month and older.

Overdose.

Symptoms. In cases of significant overdose, particularly in patients with impaired renal function, adverse reactions may intensify. 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 cefepime elimination 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:

Uncommon: oral candidiasis, vaginal infections;
Rare: candidiasis.

Blood and lymphatic system disorders:

Very common: positive Coombs test;
Common: prolonged prothrombin time or partial thromboplastin time (PTT), anemia, eosinophilia;
Uncommon: thrombocytopenia, leukopenia, neutropenia;
Frequency not known: aplastic anemia¹, hemolytic anemia¹, agranulocytosis.

Immune system disorders:

Rare: hypersensitivity reactions, including anaphylaxis, angioedema;
Frequency not known: anaphylactic shock.

Metabolism and nutrition disorders:

Frequency not known: pseudopositive urine glucose test.

Psychiatric disorders:

Frequency not known: confusion, hallucinations.

Nervous system disorders:

Uncommon: headache;
Rare: seizures, paresthesia, dysgeusia, dizziness;
Frequency not known: insomnia, restlessness, epileptiform seizures, encephalopathy (loss of consciousness, hallucinations, stupor, coma), myoclonus, altered state of consciousness.

Cardiac disorders:

Rare: vasodilation;
Frequency not known: tachycardia, bleeding¹.

Respiratory system disorders:

Rare: respiratory disorders;
Frequency not known: cough, sore throat, dyspnea.

Gastrointestinal disorders:

Common: diarrhea;
Uncommon: colitis, pseudomembranous colitis, nausea, vomiting;
Rare: abdominal pain, constipation;
Frequency not known: dyspepsia, gastrointestinal disorders.

Hepatobiliary disorders:

Common: increased levels of alanine aminotransferase, aspartate aminotransferase, total bilirubin;
Frequency not known: hepatitis, cholestatic jaundice.

Skin and subcutaneous tissue disorders:

Common: rash;
Uncommon: pruritus, urticaria, erythema;
Frequency not known: Stevens-Johnson syndrome¹, erythema multiforme¹, toxic epidermal necrolysis¹.

Renal and urinary disorders:

Uncommon: increased blood urea nitrogen, increased serum creatinine;
Frequency not known: renal failure, nephrotoxicity.

Reproductive system and breast disorders:

Rare: genital pruritus.

General disorders and administration site conditions:

Common: infusion site reactions, injection site pain, injection site inflammation;
Uncommon: fever, infusion site inflammation;
Rare: chills;
Frequency not known: phlebitis.

Investigations:

Frequency not known: increased alkaline phosphatase levels, transient increase in blood urea nitrogen and/or serum creatinine, transient leukopenia, neutropenia, agranulocytosis, transient thrombocytopenia.

Other:

Frequency not known: asthenia, increased sweating, vaginitis, chest pain, back pain, peripheral edema.

Possible adverse reactions characteristic of cephalosporin antibiotics: aplastic anemia, hemolytic anemia, bleeding, liver function disorders, cholestasis, pancytopenia.

¹ Adverse reactions reported with other drugs of this class.

Pediatric patients

The safety profile of cefepime in pediatric patients is similar to that in adults.

The most commonly reported adverse reaction in clinical trials is rash.

Reporting of adverse reactions

Reporting suspected adverse reactions after drug 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, are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at: https://aisf.dec.gov.ua.

Shelf life

2 years.

Storage conditions

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

Reconstituted solutions are stable for 7 days when stored at 2–8 °C.

Incompatibilities

Do not mix with other medicinal products in the same container. Use only the solvents specified in the section "Dosage and administration".

Packaging

Powder in a glass vial sealed with a rubber stopper and aluminum flip-off cap, with 1 or 10 vials per carton labeled in Ukrainian.

Prescription status

Prescription only.

Manufacturer

Ananta Medicare Limited.

Manufacturer's address

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.