INSTRUCTION

for medical use of the medicinal product

DENIPIME

 

Composition:

active substance: cefepime;

1 vial contains cefepime hydrochloride, equivalent to cefepime 1000 mg (as a sterile mixture of cefepime hydrochloride and L-arginine);

excipient: L-arginine (in a sterile mixture with cefepime hydrochloride).                                                                                         

 

Pharmaceutical form. Powder for solution for injection.

Basic physical and chemical properties: white to light yellow powder.

 

Pharmacotherapeutic group.

Antibacterial agents for systemic use. Other β-lactam antibiotics. Fourth generation cephalosporins. ATC Code: J01D E01.

 

Pharmacological properties.

Pharmacodynamics.

Cefepime inhibits bacterial cell wall synthesis and has a broad-spectrum activity against various gram-positive and gram-negative bacteria. Cefepime is stable to hydrolysis by most b-lactamases, including chromosomally-mediated b-lactamases, and rapidly penetrates gram-negative bacteria.

Cefepime is active against such microorganisms:

gram-positive aerobes:  

Staphylococcus aureus and Staphylococcus epidermidis (including their b-lactamase-producing strains); other staphylococcus strains, including S. hominis, S. saprophyticus; Streptococcus pyogenes (group A streptococci); Streptococcus agalactiae (group B streptococci); Streptococcus pneumoniae (including strains with moderate resistance to penicillin – minimum inhibitory concentration (MIC) from 0.1 to 1 µg/ml); other b-hemolytic streptococci (groups C, G, F), S. bovis (group D), Viridans streptococci. Most enterococci strains, for example, Enterecoccus faecalis, and staphylococci resistant to methicillin, are resistant to most cephalosporins, 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 b-lactamase-producing strains); H. parainfluenzae; Hafnia alvei; Legionella spp.; Morganella morganii; Moraxella catarrhalis (Branhamella catarrhalis) (including b-lactamase-producing strains); Neisseria gonorrhoeae (including b-lactamase-producing strains); N. meningitidis; Pantoea agglomerans (known as Enterobacter agglomerans); 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 maltophilia and Pseudomonas  maltophilia;

anaerobes:

Bacteroides spp., including B. melaninogenicus and other microorganisms of the oral cavity that belong to Bacteroides; Clostridium perfringens; Fusobacterium spp.; Mobiluncus spp.; Peptostreptococcus spp.; Veillonella spp. Cefepime is inactive against Bacteroides fragilis and Clostridium difficile.

Pharmacokinetics.

Table 1 represents average cefepime blood plasma concentrations in healthy adult men after different periods of time after single intravenous and intramuscular administrations.

Table 1.

Average cefepime blood plasma concentrations (µg/ml)

Cefepime dose	0.5 hours	1 hour	2 hours	4 hours	8 hours	12 hours
1 g i.v.	78.7	44.5	24.3	10.5	2.4	0.6
1 g i.m.	14.8	25.9	26.3	16.0	4.5	1.4

 

Therapeutic concentrations of cefepime are also achieved in urine, bile, peritoneal fluid, bronchial secretion, sputum, prostate, appendix, and gallbladder.

The average cefepime elimination half-life is approximately 2 hours. In healthy volunteers receiving intravenous doses of 2 g with an interval of 8 hours during 9 days, no drug cumulation in the body was observed.

Cefepime is metabolized into N-methylpyrrolidine, which rapidly transforms into N-methylpyrrolidine oxide. The average general clearance is 120 ml/min. Cefepime is excreted almost solely by the renal system, mainly through glomerular filtration (average renal clearance – 110 ml/min). About 85% of administered dose is excreted in the urine as unchanged cefepime, 1 % of N-methylpyrrolidine, about 6.8 % of N-metthylpyrrolidine oxide, and about 2.5 % of an epimer of cefepime.  Plasma protein binding is less than 19 % and is not associated with the drug concentration in blood plasma.

In elderly patients over 65 years of age with normal renal function, no Cefepime Ananta dose adjustment is needed, despite the lower value of renal clearance in comparison to younger patients.

Studies conducted in patients with different levels of renal impairment, demonstrated an increase in elimination half-life. The average elimination half-life in patients with severe renal impairment, who require treatment through dialysis, is 13 hours at haemodialysis and 19 hours at peritoneal dialysis. 

There are no changes in cefepime’s pharmacokinetics in patients with impaired renal function or cystic fibrosis. There is no need for dose adjustment in such patients. 

 

Clinical particulars.

Indications.

Adults.

Infections, caused by microorganisms susceptible to the drug:  

– respiratory tract infections, including pneumonia, bronchitis;

– skin and subcutaneous tissue infections;

– intra-abdominal infections, including peritonitis and biliary tract infections;

– urinary tract infections, including pyelonephritis;

– gynecological infections;

– septicaemia.

Empirical treatment of patients with neutropenic fever.

Prophylaxis of postoperative complications in intra-abdominal surgery.

Children.

– Pneumonia;

– urinary tract infections, including pyelonephritis;

– skin and subcutaneous tissue infections;

– septicaemia;

– empirical treatment of patients with neutropenic fever;

– bacterial meningitis.

 

Contraindications.

Hypersensitivity to cefepime or arginine, and to other cephalosporins, penicillins or other β-lactam antibiotics.

 

Special precautions.

Ingress of the medicinal product into the external environment should be minimized. Ingress of the medicinal product into the sewage or household waste should be avoided.

 

Interaction with other medicinal products and other forms of interaction.

If high doses of aminoglycosides are used concomitantly with cefepime, renal function should be constantly monitored due to potential nephrotoxicity and ototoxicity of aminoglycosides. Nephrotoxicity has also been reported after concomitant use of other cephalosporins and diuretics, e.g. furosemide.

Cefepime in concentrations from 1 to 40 mg/ml is compatible with such parenteral solutions: 

0,9 % sodium chloride solution for injections; 5 and 10 % glucose solutions for injection; 6 M sodium lactate solution for injection; 5 % glucose and 0.9 % sodium chloride solution for injection; Ringer’s solution with lactate and 5% glucose solution for injection.  

To avoid possible pharmaceutical interaction of cefepime with other medicinal products, cefepime solution (like many other b-lactam antibiotics) should not be administered concomitantly with metronidazole, vancomycin, gentamicin, tobramycinum sulphate and netilmicin sulphate. In case cefepime is prescribed along with the abovementioned agents, each antibiotic should be administered separately.

Effect on laboratory tests’ results  

Use of cefepime can lead to false-positive results of urine glucose test in case Benedict’s reagent is used. Glucose tests based on the enzyme glucose oxidase are recommended for use.  

 

Precautions for use. 

For patients with a high risk of severe infections (e.g., patients with a history of bone marrow transplantation with reduced activity occurring in the setting of malignant haemolytic disease with severe progressive neutropenia), monotherapy may not be sufficient. Therefore, a complex antimicrobial therapy is indicated.

It is necessary to determine whether the patient previously had any immediate hypersensitivity reactions to cefepime, cephalosporins, penicillins, or other b-lactam antibiotics. Antibiotics should be prescribed with caution to all the patients with any forms of allergies, especially to medicinal agents. If an allergy occurs, the use of the drug should be discontinued. Severe immediate hypersensitivity reactions might require adrenaline use or other forms of therapy.  

Cases of pseudomembranous colitis have been reported with almost all broad-spectrum antibiotics. Therefore, it is important to consider the possibility of developing this pathology in case of diarrhoea during treatment with cefepime. Pseudomembranous colitis may range from mild diarrhoea to fatal colitis. Mild forms of colitis were reversible and disappeared after discontinuation of cefepime; moderate or severe conditions may require special treatment.

Caution should be exercised in patients with digestive tract diseases, particularly colitis.

During prolonged treatment, it is necessary to regularly monitor the functional parameters of the liver, kidneys and haemopoietic organs.

For patients with impaired renal function (creatinine clearance ≤ 60 ml/min), cefepime dose should be adjusted to compensate for the slow rate of renal excretion.  As prolonged antibiotic serum concentrations might occur in patients with renal failure or other states that may negatively affect renal function, the maintenance dose should be decreased in case cefepime is administered to such patients. The level of renal function impairment, severity of the infection, susceptibility to organisms that caused the infection should be considered for the determination of the next dose.

During the treatment with cefepime, similarly to the other drugs of the group, severe adverse reactions like reversible encephalopathy (confusion, including disorganized thinking), myoclonia, seizures, and/or renal impairment, have mostly been observed in patients with renal failure, who received doses higher than recommended, and in elderly patients with renal failure who received cefepime at recommended doses. Sometimes such reactions were observed in those patients who received doses adjusted accordingly to their renal function. In most cases, symptoms of nephrotoxicity were reversible and disappeared after the discontinuance of the treatment and/or after haemodialysis. 

Cefepime’s pharmacokinetics does not change in patients with impaired renal function. No dose adjustment is needed for such patients.

Use of antibacterial agents causes changes in normal flora of the colon and may lead to excessive growth of clostridia. Studies show that the toxin, produced by Clostridium difficile, is the main cause of antibiotic-associated colitis. After the diagnosis of pseudomembranous colitis is confirmed, therapeutic measures should be taken. Pseudomembranous colitis of moderate severity might disappear after the discontinuance of the treatment. If moderate or severe pseudomembranous colitis occurs, it is necessary to consider using fluids and electrolytes, overcoming the lack of proteins, and administering antibacterial agent effective against Clostridium difficile.

Warning.

It is unlikely that prescribing cefepime in case no bacterial infection is found or suspected, or administering cefepime as a precaution, would be useful, however, it increases the risk of emergence of bacteria insusceptible to this medicinal agent. Long-term use of cefepime (like other antibiotics) may lead to the development of superinfection. A re-examination of the patient’s state is recommended. In case superinfection is developed, adequate measures should be taken.

Many cephalosporins, including cefepime, are associated with the decrease in prothrombin activity. Patients with impaired liver or renal function, malnourished patients, and those who receive continuous treatment with antimicrobial therapy are at risk. It is important to control the prothrombin level in patients at risk, and if necessary vitamin K should be prescribed.

During the treatment with cefepime, positive direct Coombs test results might be obtained. During haematological or transfusional procedures for blood typing with a cross-match test, when antiglobulin test or Coombs test are carried out in new-borns, whose mothers received treatment with cephalosporins before delivery, it is necessary to consider that positive Coombs test might be the result of treatment with the drug. 

When lidocaine is used as a solvent in children, it is necessary to keep in mind the information regarding lidocaine’s safety.

It has been proven that L-arginine changes glucose metabolism and increases blood serum potassium levels at doses that are 33 times higher than maximum recommended dose of cefepime. The effects at lower doses are currently unknown.

 

Pregnancy or lactation.

Adequate and well-controlled studies with pregnant women have not been carried out, so cefepime should be prescribed during pregnancy only if the expected benefit to the woman outweighs the potential risk to the foetus.

Cefepime excretes into breast milk in very small amounts, so breastfeeding should be discontinued during treatment.

 

Effects on reaction rate while driving vehicles or operating other machinery.

As CNS adverse reactions might occur during the treatment, it is better to avoid driving vehicles or operating other machinery.

 

Methods of administration and dosage. 

The normal dose for adults is 1 g, and it should be administered intramuscularly or intravenously with an interval of 12 hours. The normal duration of the treatment is 7-10 days; severe infections might require treatment that is more continuous.

However, dosage and route of administration may vary depending on the susceptibility of pathogens, severity of the infection, and the functional state of the patient’s kidneys.

Dosage recommendations for adults are given in Table 2.

Table 2

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 interventions.

In adults, 60 minutes before the start of surgery, 2 g of the drug should be intravenously administered for 30 minutes. After that, 500 mg of metronidazole should be administered intravenously. Metronidazole solutions should not be administered concomitantly with cefepime. The infusion system should be flushed before administering metronidazole.

During prolonged (more than 12 hours) surgical operations, 12 hours after the first dose, it is recommended to repeat an equal dose of the drug followed by metronidazole.

Impaired renal function. In patients with impaired renal function (creatinine clearance less than 30 ml/min), the cefepime dose should be adjusted.

Table 3

 

Recommended cefepime doses for adults

Creatinine clearance (ml/min)	Recommended doses
> 50	Usual dosage according to the infection severity (see previous table), no dose adjustment is needed
	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 the 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
Haemodialysis*	500 mg every 24 hours	500 mg every 24 hours	500 mg every 24 hours	500 mg every 24 hours

^*On haemodialysis days, cefepime should be administered after haemodialysis.

If only creatinine concentration in blood serum is known, then creatinine clearance can be determined via the following formula:

Men:

creatinine clearance (ml/min) =	body weight (kg) ´ (140 - age)
	72 ´ serum creatinine (mg/dl)

Women:

creatinine clearance (ml/min) = the abovementioned value ´ 0,85.

 

At haemodialysis, approximately 68% of the drug dose is excreted within 3 hours. After each haemodialysis session is over, a repeated dose equal to the initial dose should be administered. At CAPD, the drug can be used in initial normal recommended doses of 500 mg, 1 g or 2 g depending on the severity of the infection with an interval of 48 hours between the administrations.

Children aged from 1 to 2 month. Children aged 1-2 months should be prescribed only for vital indications. The condition of children under 40 kg receiving cefepime should be monitored continuously.

In children with impaired renal function, it is recommended to reduce the dose or increase the interval between doses.

 

Calculation of the creatinine clearance values in children:

 

creatinine clearance (ml/min/1.73 m2) =	0,55 ´ height (cm)
	serum creatinine (mg/dl)

or

creatinine clearance (ml/min/1.73 m2) =	0,52 ´ height (cm)	− 3,6
	serum creatinine (mg/dl)

 

Children aged 1 to 2 months. Cefepime is prescribed only for vital indications at a dose of 30 mg/kg body weight every 12 or 8 hours, depending on the infection severity.

Children aged from 2 months. The maximum dose for children should not exceed the recommended dose for adults. The usual recommended dose for children with body weight under 40 kg in case of complicated or uncomplicated urinary tract infections (including pyelonephritis), uncomplicated skin infections, pneumonia, and also in case of empiric treatment of febrile neutropenia is 50 mg/kg every 12 hours (patients with febrile neutropenia and bacterial meningitis – every 8 hours). The usual durations of the treatment is 7-10 days, severe infections might require longer treatment.  

In children with body weight of more than 40 kg, cefepime is prescribed in the doses recommended for adults.

Drug administration. Denipime should be administered intravenously or via a deep intramuscular injection into muscles (for example, into the upper outer quadrant of the gluteus maximus).  

Intravenous administration. Intravenous administration is better for patients with severe or life-threatening infections.

At intravenous administration, cefepime should be dissolved in sterile water for injections, in 5% glucose solution for injections or 0.9% sodium chloride solution for injections with 5% glucose or without it, as indicated in the table below. It should be administered slowly intravenously during 3-5 minutes or through a system for intravenous administration.

Intramuscular administration. Denipime should be dissolved in sterile water for injection, bacteriostatic water for injection with paraben or benzyl alcohol, 0.5% or 1% lidocaine hydrochloride solution in concentrations indicated in the table 4. 

If lidocaine is used as a solvent, the lidocaine tolerance skin test should be carried out.

 

Table 4

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

Just like other medicinal agents, which are administered parenterally, prepared solutions of the drug should be carefully checked for any impurities.

For the identification of pathogen(s) and determination of susceptibility to cefepime, appropriate microbiological studies should be carried out. However, cefepime can be used as monotherapy even before the identification of pathogen microorganism, as it has a broad spectrum of action against gram-positive and gram-negative microorganisms. In patients at risk of mixed aerobic-anaerobic (including Bacteroides fragilis) infections, treatment with the drug may be started before the identification of pathogen, along with the drug that is active against anaerobes.  

 

Children.

Use for children from 1 month of age.

 

Overdose.

Symptoms: in case the doses administered exceed the recommended ones significantly, especially in patients with impaired renal function, adverse reactions manifestations might intensify. The overdose symptoms include encephalopathy with hallucinations, confusion, stupor, coma, myoclonia, epileptiform seizures, neuromuscular excitability.   

Treatment. Treatment with the drug should be discontinued; symptomatic therapy should be carried out. Haemodialysis hastens cefepime excretion from the body; peritoneal dialysis is ineffective. Severe immediate allergic reactions require use of adrenaline and other forms of intensive therapy.

 

Adverse reactions.

Infections and infestations: oral candidiasis, vaginitis, candidiasis.

Blood and lymphatic system disorders: anaemia, eosinophilia, transient leukaemia, neutropenia, agranulocytosis, thrombocytopenia.

Immune system disorders: hypersensitivity reactions, including anaphylaxis, anaphylactic shock, angioedema.

Respiratory system disorders: cough, sore throat, dyspnoea, respiratory distress.

Cardiovascular system disorders: tachycardia, vasodilation.

Digestive tract disorders: nausea, vomiting, dyspepsia, change in taste, diarrhoea, colitis (including pseudomembranous colitis), abdominal pain, constipation.

Nervous system disorders: dizziness, headache, anxiety, insomnia, paresthesia, confusion/loss of consciousness, convulsions/epileptiform seizures, myoclonus, encephalopathy, hallucinations, stupor, coma.

Hepatobiliary system disorders: hepatitis, cholestatic jaundice.

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

Reproductive system disorders: genital itching.

Urinary system disorders: renal failure.

Other: asthenia, excessive sweating, fever, erythema, chest pain, back pain, peripheral edema.

Local reactions at the injection site:

in case of intravenous administration - phlebitis and inflammation;

in case of intramuscular administration - pain, inflammation.

Post-marketing studies:

- encephalopathy (loss of consciousness, hallucinations, stupor, coma), epileptiform seizures, myoclonus, renal failure;

- anaphylaxis, including anaphylactic shock, transient leukaemia, neutropenia, agranulocytosis and thrombocytopenia.

Investigations: increased levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, anaemia, eosinophilia, increased prothrombin time or partial thromboplastin time (PTT) and a positive Coombs test without haemolysis. Temporary increases in blood urea nitrogen and/or serum creatinine and transient thrombocytopenia were observed in less than 0.5% of patients. Transient leukopenia and neutropenia have also been reported.

Possible adverse reactions characteristic of cephalosporin antibiotics include Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, toxic nephropathy, aplastic anaemia, haemolytic anaemia, bleeding, liver dysfunction, cholestasis, pancytopenia. 

 

Shelf-life. 2 years.

Do not use after the expiry date indicated on the packaging.

 

Storage conditions.

Keep out of reach of children.

Store in the original package at temperature not exceeding 25 °С.

After preparation, the solution should be used immediately after dilution or stored for not more than 24 hours at 25°C and 7 days at 2-8°C.

Discolouration does not affect the activity of the drug, provided that the drug is stored properly as recommended by the manufacturer.

 

Incompatibility.

Do not mix with other drugs in the same container, Use solvents listed in the section «Routes of administration and dosage. »

 

Packaging.

1000 mg powder for injection in a vial No. 1 in a cardboard box.

 

Terms of dispensing.

On prescription.

 

 

Date of last review. 10.02.2025