INSTRUCTION

for medical use of the preparation

CEFOTRINE

Composition:

Active substance: cefepime hydrochloride USP equivalent to cefepime;

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

Auxiliary substance: L-arginine.

Medical form. Powder for preparation of the solution for injections.

Pharmacotherapeutical group.

Antibacterial agents for systemic use. β-lactam antibiotics. Cephalosporins of the IV generation. АТС code J01D E01.

Clinical characteristics.

Indications.

Adults.

Infections, caused by microflora susceptible to the preparation:

– infections of respiratory ways, including pneumonia and bronchitis;

– infections of skin, subcutaneous fat and soft tissues;

– intraabdominal infections, including peritonitis and infections biliary tracts;

– gynaecological infections;

– septicemia.

Empirical therapy for patients with neutropenic fever.

Prevention of post-operational complications in intraabdominal surgery.

Children.

– Pneumonia;

– infections of urinary tracts, including pyelonephritis;

– infections of skin and subcutaneous fat;

– septicemia;

– empirical therapy for patients with neutropenic fever;

– bacterial meningitis.

Contraindications.

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

Way of administration and doses.

It is necessary to carry out a skin test for tolerance before the use of the preparation.

Usual dose for adults is 1 g, which is administrated intravenously or intramuscularly with a 12-hour interval. Usual duration of treatment course is 7 - 10 days; severe infections may require a longer duration of treatment.

However, dosage and way of administration vary due to sensitivity of causative agents, severity of the infection, as well as functional state of patient’s kidneys.

Recommendations as for Cefotrine dosages for adults are given in the table below. 

Infections of urinary tracts of mild and medium severity	500 mg - 1 g intravenously or intramuscularly	every 12 hours
Other infections of mild and medium severity	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

For prevention of infection development at surgical interventions. Adults are introduced 2 g of the preparation intravenously for 30 min 60 min before the surgery. Then they are additionally introduced 500 mg of metronidazole intravenously. Metronidazole solutions should not be introduced concomitantly with Cefotrine. The system for infusions should be washed before metronidazole introduction.

During long-term (over 12 hours) surgeries, it is recommended to carry out repeated introduction of the same Cefotrine dose in 12 hours followed by metronidazole introduction.

Renal dysfunction. In patients with renal dysfunction (creatinine clearance less than 30 ml/min), the dose of Cefotrine should be adjusted.

Recommended doses of cefepime for adults

Creatinine clearance (ml/min)	Recommended doses
> 50	Usual dosage due to infection severity (see the previous table), dose adjustment is not necessary
	2 g every 8 hours	2 g every 12 hours	1 g every 12 hours	500 mg every 12 hours
30 - 50	Dose adjustment due 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 creatinine concentration in serum is known, creatinine clearance can be calculated according to the following formula:

Men:

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

 

Women:

creatinine clearance (ml/min) = the value above ´ 0.85.

In case of hemodialysis, about 68 % of the dose of the preparation is excreted from the organism in 3 hours. After the end of each dialysis session it is necessary to introduce the repeated dose, which is equal to the initial one. In case of continuous outpatient peritoneal dialysis, the preparation may be used in initial normal recommended doses of 500 mg, 1 or 2 g due to the severity of the infection with 48-hour intervals between the doses.

Children aged 1 to 2 months. Indicated only due to vital indications as 30 mg/kg of body weight every 12 or 8 hours, due to the severity of the infection. The state of children with body weight below 40 kg, who receive Cefotrine treatment, should be closely monitored.

In children with renal dysfunction it is recommended to decrease the dose or increase the interval between introductions.

The calculation of clearance creatinine 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)  /  serum creatinine (mg/dl)  - 3.6

Children over 2 months. Maximal dose for children should not exceed the recommended dose for adults. Usual recommended dose for children with bodyweight under 40 kg in case of complicated or non-complicated urinary tracts infections (including pyelonephritis), in case of non-complicated skin infections, pneumonia, as well as in case of empirical treatment of febrile neutropenia is 50 mg/kg every 12 hours (for patients with febrile neutropenia and bacterial meningitis - every 8 hours). Usual duration of treatment is 7 - 10 days, severe infections may require a longer treatment.

In children with bodyweight of 40 kg and over, Cefotrine is indicated similar to adults.

Introduction of the preparation. Cefotrine can be introduced intravenously or via deep intramuscular injection into a large muscle mass (for example, into the upper external quadrant of the sciatic muscle – gluteus maximus).

Intravenous introduction. Intravenous way of introduction is better for patients with severe or life-threatening infections.

In case of intravenous way of introduction Cefotrine is diluted in sterile water for injections, in 5 % glucose solution for injections or 0.9 % solution of sodium chloride, as indicated in the table below. The preparation is introduced intravenously slowly for 3 - 5 min or via a system for intravenous introduction.

Intramuscular introduction. Cefotrine can be diluted in sterile water for injections, 0.9 % solution of sodium chloride for injections, 5 % glucose solution for injections, bacteriostatic water for injections with paraben or benzyl alcohol, 0.5 % or 1 % solution of lidocaine hydrochloride in concentration that are indicated in the table below.

If lidocaine is used as a diluent, it is necessary to carry out skin test for tolerance before the introduction.

 

	Volume of the solution for diluting (ml)	Approximate volume of the obtained solution (ml)	Approximate concentration of cefepime (mg/ml)
Intravenous introduction: 1 g/vial	10	11.4	90
Intramuscular introduction: 1 g/vial	3	4.4	230

Similar to other medicinal preparations that are used via parenteral introduction, reconstituted solutions of the preparation should be checked for absence of any mechanical inclusions before the introduction.

For identification of causative agent(s) and determination of its(their) sensitivity to cefepime, it is necessary to carry out appropriate microbiological investigations. However, Cefotrine may be used as monotherapy before causative agent identification, as it has a broad spectrum of antibacterial action against gram-positive and gram-negative microorganisms. In patients with a risk of mixed aerobic-anaerobic (includingBacteroides fragilis) infection, treatment with Cefotrine may be initiated before causative agent identification in combination with the preparation that influences anaerobes.

Side effects.

With frequency between 0.1 % and 1 %:

hypersensitivity: itch, urticaria;

From the side of gastrointestinal tract: nausea, vomiting, mouth candidosis, diarrhea, colitis (including pseudomembranous colitis);

From the side of the central nervous system: headache;

other: fever, vaginitis, erythema.

With frequency between 0.05 % and 0.1 %: abdominal pain, constipation, vasodilation, breathing disorders, dizziness, paresthesia, genital itch, fever and candidosis.

With frequency less than 0.05 %: anaphylactic reaction and epileptiform seizures.

Local reactions at the site of introduction of the preparation: in case of intravenous introduction – phlebitis and inflammation;

in case of intramuscular introduction – pain, inflammation.

Post-marketing investigations:

– encephalopathy (loss of consciousness, hallucinations, stupor, coma), epileptiform seizures, myoclonia, renal insufficiency;

– anaphylactic reaction, including anaphylactic shock, transient leukopenia, neutropenia, agranulocytosis and thrombocytopenia.

Laboratory indexes: increased levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, anemia, eosinophilia, increased prothrombin time or partial thromboplastin time (PTT) and positive result of Coombs' Test without hemolysis. Temporal increases of blood urea and/or serum creatinine and transient thrombocytopenia have been noted in less than 0.5 % patients. Transient leukopenia and neutropenia have also been noted.

Overdose.

Symptoms: in case of significant exceeding of the recommended doses, especially in patients with renal dysfunction, the manifestations of side effects increase. Overdose symptoms include encephalopathy, which is accompanied by hallucinations, impairment of consciousness, stupor, coma, myoclonia, epileptiform seizures, neuromuscular excitability.

Treatment. Introduction of the preparation should be discontinued. It is necessary to carry out symptomatic treatment. Use of hemodialysis promotes cefepime excretion from the organism; peritoneal dialysis is ineffective. Severe allergic reactions of immediate type require the use of adrenaline and other forms of intensive therapy.

Use during pregnancy and lactation.

Animal studies have demonstrated the absence of any influence on reproductive function and absence of any harmful influence on the fetus. However, adequate and well-controlled studies in pregnant women have not been conducted, that is why Cefotrine may be indicated during pregnancy only when the expected benefit for the mother overcomes potential risk for the fetus.

Cefepime is excreted in breast milk in very small quantity; however, during therapy with the preparation breast feeding should be discontinued.

Children.

Used in children aged over 1 month.

Peculiarities of the use.

In patients with high risk of severe infections (for example, in patients with a history of bone marrow transplantation in case of its decreased activity at the background of malignant hemolytic pathology with severe progressing neutropenia) monotherapy may be insufficient, that is why complex antimicrobial therapy is indicated.

It is necessary to determine exactly, if the patient has previously had any reactions of hypersensitivity of immediate type to cefepime, cephalosporins, penicillins or other b-lactam antibiotics. Antibiotics should be indicated with caution to all patients with any forms of allergy, especially to medicinal preparations. In case of allergic reaction development, use of the preparation shoud be discontinued. Severe hypersensitivity reactions of immediate type may require the use of adrenaline and other forms of therapy.

In case of administration of practically any antibiotic of broad spectrum of actions, there have been reports on cases of pseudomembranous colitis. That is why it is important to take into consideration the possibility of development of this pathology in case of diarrhea development during Cefotrine therapy. Mild forms of colitis may resolve after use of the preparation; moderate or severe states may require special treatment.

Similar to other antibiotics, use of the preparation Cefotrine may lead to colonization by insensitive microflora. In case of superinfection development during the treatment, appropriate measures should be taken.

Ability to influence the reaction rate when driving or operating other mechanisms.

Taken into consideration the possibility of the influence of the preparation on the central nervous system, it is recommended to abstain from driving and working with other mechanisms during Cefotrine use.

Interaction with other medicinal preparations and other forms of interactions.

In case of administration of high doses of aminoglycosides concomitantly with Cefotrine, it is necessary to conduct close monitoring of renal function due to potential nephrotoxicity and ototoxicity of aminoglycoside antibiotics. Nephrotoxicity has been noted after concomitant use of other cephalosporins with diuretics, such as furosemide.

Cefepime in concentration between 1 and 40 mg/ml is compatible with the following parenteral solutions:

0.9 % solution of sodium chloride for injections; 5 and 10 % glucose solution for injections; solution of 6M sodium lactate for injections, solution of 5 % glucose and 0.9 % sodium chloride for injections; Ringer's solution with lactate and 5 % glucose solution for injections.

In order to avoid possible drug interaction with other medicinal preparations, cefepime solutions (similar to most other b-lactam antibiotics) are not introduced concomitantly with the solutions of metronidazole, vancomycin, gentamicin, tobramicin sulphate and netilmicin sulphate. If Cefotrine із indicated with the mentioned preparations, each antibiotic is introduced separately.

Pharmacological properties.

Pharmacodynamics. Cefepime inhibits the synthesis of bacterial cell wall enzymes and has a broad spectrum of action against different gram-positive and gram-negative bacteria. Cefepime is highly resistant to hydrolysis of most b-lactameses, it has minor affinity as for b- lactameses, which is encoded by chromosome gens, and penetrates quickly into gram-negative bacteria cells.

Cefepime is active against the following microorganisms:

Gram-positive aerobes: Staphylococcus aureus and Staphylococcus epidermidis (including their strains that produce b-lactamase); other staphylococci strains, includingS. hominis, S. saprophyticus; Streptococcus pyogenes (streptococci of Group А);Streptococcus agalactiae (streptococci of Group В); Streptococcus pneumoniae (including strains with medium resistance to penicillins - MIC between 0.1 and 1 µg/ml); other b-hemolytic streptococci (Groups C, G, F), S. bovis (Group D), streptococci of GroupViridans (most of enterecocci strains, for example, Enterecoccus faecalis, and staphylococci resistant to methicillin, 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; Proteusspp., 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 strains that produce -lactamase); H. parainfluenzae; Hafnia alvei; Legionella spp.; Morganella morganii; Moraxella catarrhalis (Branhamella catarrhalis) (including strains that produce b-lactamase); Neisseria gonorrhoeae(including strains that produce b-lactamase); N. meningitidis; Pantoea agglomerans (known as Enterobacter agglomerans); Providencia spp. (including P. rettgeri, P. stuartii); Salmonella spp.; Serratia (including S. marcescens, S. liquefaciens); Shigellaspp.; 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, which belong 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 male adults in various times after single intravenous and intramuscular introduction are given in the table below.

Plasma concentrations of cefepime (µg/ml) at intravenous (i/v) and intramuscular (i/m) introduction

Cefepime dose	0.5 hour	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, bronchi mucin, sputum, prostate, appendix and cholecyst.

Mean cefepime half-life period is about 2 hours. In healthy volunteers, who received doses up to 2 g intravenously with 8-hour intervals for 9 days, no accumulation of the preparation in the organism has been observed.

Cefepime is metabolized into N-methylpyrrolidine, which transforms quickly into N-methylpyrrolidine oxide. Mean general clearance is 120 ml/min. Cefepime is excreted almost exclusively at the expense of renal regulation mechanisms, mainly via glomerular filtration (mean renal clearance is 110 ml/min). About 85 % of the used dose is found in urine in the form of unchanged cefepime, 1 % - of N- methylpyrrolidine, about 6.8 % - of N-methylpyrrolidine oxide and about 2.5 % - of cefepime epimer. Plasma protein binding of cefepime is less 19 % and is not related to serum concentration of the preparation.

In patients over 65 with normal renal function, Cefotrine dose adjustment is not necessary in spite of less value of renal clearance in comparison with younger patients.

Studies involving patients with different degree of renal insufficiency have demonstrated increase in half-life period. On average, half-life period in patients with severe renal dysfunction, who require treatment via dialysis, is 13 hours at hemodialysis and 19 hours – at peritoneal dialysis.

Cefepime pharmacokinetics in patients with disturbed liver function or mucoviscidosis is not changed. No dose adjustment is necessary in such patients.

The dose of the preparation is 50 mg/kg of body weight at intravenous introduction for 5 to 20 min every 8 hours.

Pharmaceutical characteristics.

Main physical and chemical properties: powder from white or pale yellow color.

Shelf life.

3 years.

Conditions of storage.

Store at temperature below 25 °С in the original package. Keep out of the reach of children.

Package.

1 g of cefepime in a vial, 1 vial in a carton.

Category of dispensing.

On prescription.

Manufacturer.

Marksans Pharma Ltd.

Location.

Floor 21, Lotus Business Park, Off New Link Road, Andheri (West), Mumbai – 400053, India;

Village Thana, Baddi, Solan, Himachal Pradesh – 173205, India.

Applicant.

Ananta Medicare Ltd.

Location.

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

Date of the last review. 23.02.12