INSTRUCTION

for medical use of the medicinal product

CEFEPIME ANANTA

Composition:

Active substance: cefepime;

1 vial contains 1 g or 2 g of cefepime as cefepime hydrochloride;

Inactive substance: L-arginine.                                                                                         

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. Cefepime.

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 mkg/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, resistant to most cephalosporines, 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 (mkg/ml)

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. 

The drug dose is 50 mg/kg body weight at intravenous introduction during from 5 to 20 minutes every 8 hours.

Children.

Inchildrenagedfrom 2 monthsto 11 yearsafterasingleintravenousintroduction, thegeneralclearanceandthevolumeofdistributionina steady state is 3.3 (± 1.0) ml/min/kg

and 0,3 (± 0,1) l/kg, respectively.  

Around 60,4 (± 30,4) % of the administered cefepime dose is excreted in the urine unchanged, renal clearance is 2,0 (± 1,1) ml/min/kg. After intramuscular administration, the maximum cefepime concentration in blood plasma in a steady state is approximately 68 mkg/ml in 0.75 hours. In 8 hours after the intramuscular administration, the cefepime blood plasma concentration reaches 6 mkg/ml. Absolute bioavailability after cefepime intramuscular administration is approximately 82%. The patients’ age and sex do not influence the drug clearance.

Table 2

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

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

The drug dose of 50 mg/kg body weight at intravenous administration during 5-20 minutes every 8 hours. The blood plasma and CSF concentrations were measured at the end of administration on either 2 or 3 day of treatment with the drug.

Clinical particulars.

Indications.

Adults.

Infections, caused by microflora susceptible to the drug:  

– respiratory tract infections, including pneumonia;

– uncomplicated skin and subcutaneous tissue infections;

–complicated intra-abdominal infections (use in combinations with metronidazole);

– uncomplicated and complicated urinary tract infections (including pyelonephritis);

– septicaemia;

– empirical treatment of patients with neutropenic fever;

– prophylaxis of postoperative complications in intra-abdominal surgeries.

Children.

– Pneumonia;

– urinary tract infections, including pyelonephritis;

– uncomplicated skin and subcutaneous tissue infections;

– 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. 

Hypersensitivity. It is necessary to determine whether the patient previously had any immediate hypersensitivity reactions to cefepime, cefalosporins, 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, In case an allergy occurs, the use of the drug should be discontinued. Severe immediate hypersensitivity reactions might require adrenaline use or other forms of therapy.  

In patients at high risk of severe infections (for instance, in patients who previously had marrow transplantation at its low activity in the background of malignant hemolytic pathology with a severe progressing neutropenia), monotherapy might not be enough, so a combination antimicrobial therapy is indicated.

For identification of pathogen (pathogens) and assessment of susceptibility to cefepime, necessary tests should be carried out. Cefepime may be used as monotherapy before the identification of pathogen (pathogens), because it has a broad spectrum of antibacterial action against gram-positive and gram-negative microorganisms. In patients at risk of mixed aerobe-anaerobe (including Bacteroides fragilis) infection, before identifying the pathogen, treatment with the drug may be started in combination with a drug active against anaerobes.

Cephalosporines are absorbed at the red blood cells surface and react with anti-drug antibodies, which results in a positive Coombs test. In patients who used cefepime twice a day, a positive Coombs test was described without any symptoms of hemolysis.   

Glucosoria tests’s results might be false-positive. Due to that, during the treatment with the drug, urine glucose tests should be carried out by means of glucose oxidase-based methods.

At use of almost all broad spectrum antibiotics, cases of pseudomembranous colitis were reported. Therefore, during the treatment with cefepime, the possibility of such pathology’s development in case diarrhoea occurs, should be considered. Mild forms of colitis might disappear after the drug administration, medium to severe states might need special treatment. 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 descreased 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 pharmacokinetics in patients with impaired renal function does not change. No dose adjustment for such patients is needed.

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.

Precautions.

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 was proved 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.

Just like with other antibiotics, use of cefepime might lead to colonization with insusceptible microflora. In case of superinfection development during the treatment, necessary measures should be taken.  

When lidocaine is used as a solvent, it is important to consider the information regarding lidocaine safety.

Use during pregnancy or lactation.

Animaltestinghasshownnoeffectonthereproductivefunctionandnoharmfulinfluenceonfetus, however, no adequate or well-controlled studies in pregnant women have been carried out, therefore, during pregnancy cefepime can only be prescribed when the expected benefit for the mother outweighs the possible risk for the fetus.

Cefepime is exrected into breast milk in small amounts, thus, during the treatment with the drug, lactation should be stopped.

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.

Routes of administration and dosage. 

Before the drug use, a skin test for susceptibility should be carried out.

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.

Table 3

Recommendations for use of Cefepime Ananta in adults with creatinine clearance > 60 ml/min.

^*Including cases related to bacteraemia

^**Or before treating neutropenia. It is necessary to reconsider the continuance of the antibacterial therapy for the patients, who treated the fever, but have remaining symptoms of neutropenia for more than 7 days.

^***Intramuscular administration is only indicated for light and moderate uncomplicated and complicated urinary tract infections, caused by E. Coli, when intramuscular administration is considered to be more suitable for the drug introduction.  

For the prevention of the development of infections at surgical operations.

In adults, 60 min before the surgery, 2 g of the drug should be intravenously administered during 30 min. After that, 500 mg of metronidazole should be administered intravenously. Metronidazole solutions should not be administered concomitantly with cefepime. The IV system should be flushed before the administration of metronidazole.

During long (more than 12 hours) surgical operations, 12 hours after the introduction of the 1^st dose, another administration of the same cefepime dose with the following administration of metronidazole is recommended.

Impaired renal function. In patients with impaired renal function, (creatinine clearance less than 60 ml/min), the cefepime dose should be adjusted (see Table 4).

Table 4

Recommended cefepime doses in adult patients with impaired renal function

^*On haemodialysis days, cefepime should be administered after haemodialysis. Cefepime should be administered every day at the same time.  

**Continuousambulatoryperitonealdialysis

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

Men:

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. Should be used only if of vital importance in doses 30 mg/kg body weight every 12 or 8 hours, depending on the severity of the infection. The state of children with body weight under 40 kg who receive cefepime treatment, should be constantly controlled.

Calculation of the creatinine clearance values in children:

or

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.

The drug administration. Cefepime 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 Ananta 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. Cefepime Ananta should be dissolved in sterile water for injections, bacteriostatic water for injections with paraben or benzyl alcohol, 0.5% or 1% lidocaine hydrochloride solution in concentrations indicated in the table 5.  

Iflidocaineisusedasasolvent, a lidocaine toleranceskintestshould be carried out.

Justlikeothermedicinalagents, whichareadministeredparenterally, preparedsolutionsofthedrugshouldbecarefullycheckedforanyimpurities.

Таблиця 5

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.

The drug should be used in children aged from 1 month, as indicated in the section “Administration.”

When lidocaine is used as a solvent, information regarding safety of lidocaine should be considered.

In case the drug is prescribed to children aged from 1 month, the doctor should carefully assess the dose regarding the age, weight, type and severity of the infection, and renal function state.

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.

Adverse reactions are rarely observed.

Immune system: hypersensitivity reactions, including anaphylaxis, anaphylactic shock, angeoneurotic oedema; itching, rush, urticaria, fever.   

Gastrointestinal tract: diarrhoea, nausea, vomiting, oral candidiasis, dysgeusia, constipation, abdominal pain, dyspepsia, pseudomembranous colitis.

Cardiovascular system: chest pain, vasodilatation, tachycardia.

Respiratory system: cough, throat pain, dyspnoea.

Nervous system: headache, dizziness, insomnia, paraesthesia, anxiety, confusion, seizures, myoclonia, epileptiform seizures, encephalopathy (fainting, hallucinations, stupor, coma).  

Hepatobiliary system:   hepatitis, cholestatic jaundice.

Changes in laboratory tests (transient) Зміни лабораторних показників (транзиторні): increase in ALT, AST, alkaline phosphatase, total bilirubine blood plasma concentrations; temporary increase of blood urea nitrogen and/or blood serum creatinine; anemia, eozynofilia, agranulocytosis, increase in prothrombine time or in partial thromboplastin time (PTT) and positive Coombs test without haemolysis, transient thrombocytopenia, transient leukopenia and neutropenia.  

Urinary system: vaginitis, genital itching, renal impairment.

Other: asthenia, peripheral oedema, back pain, hyperhidrosis.

Reactions at injection site: at intravenous administration - phlebitis and inflammation; at intramuscular administration – inflammation or pain in injection site.

Possible adverse reactions typical for cephalosporins: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, toxic nephropathy, aplastic anaemia, haemolytic anaemia, haemorrhages, liver function impairment, cholestasis, pancytopenia.   

Storage life.

2 years.

Storage conditions.

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

Keep out of reach of children.

The prepared drug solutions are stable for 7 days if stored at temperature 2–8°С.

Incompatibility.

In order to avoid possible pharmaceutical interaction, cefepime (like most other beta-lactam antibiotics) should not be administered through the same syringe with metronidazole, vancomycin, gentamycin, tobramycin sulphate and nethylmycin sulphate. Do not mix with other drugs in the same container, Use solvents listed in the section «Routes of administration and dosage. »

Package.

Powder in a glass vial with a rubber top and aluminium flip-off cap, 1 vial in a box.

Terms of dispensing.

On prescription.

Manufacturer.

Swiss Parenterals Ltd.

Manufacturer’s registered address.

Unit ІІ, 402, 412-414 Kerala GIDC, Near Bavla, Ahmedabad, Gujarat, 382 220, India.

Applicant.

Ananta Medicare Ltd.

Applicant’s and/or declarant’s representative’s registered address.

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

Date of last review. 13.07.18.