Adzhitsef

General characteristics. Structure:

Active ingredient: 1 g of a tsefepim in the form of a tsefepim of a hydrochloride in 1 bottle.

Excipient: L-arginine.

Tsefepim – beta лактамный a tsefalosporinovy antibiotic of the IV generation of a broad spectrum of activity for parenteral use. Has bactericidal effect.

Pharmacological properties:

Pharmacodynamics. It is active concerning gram-positive and gram-negative bacteria, including the majority of the strains steady against aminoglycosides or tsefalosporinovy antibiotics of the III generation. Tsefepim suppresses synthesis of enzymes of a wall of a bacterial cell. Drug высокоустойчив to hydrolysis by beta lactamelements, has small affinity concerning the beta laktamaz coded by chromosomal genes and quickly gets into gram-negative bacterial cells.

Tsefepim is active relatively:

• gram-positive aerobes: Staphylococcus aureus, Staphylococcus epidermidis (including the strains producing beta lactamazu), Staphylococcus hominis, Staphylococcus saprophyticus, Streptococcus pyogenes (group A), Streptococcus agalactiae (group B), Streptococcus pneumoniae (including strains with average penicillin resistance – MPK from 0,1 to 0,3 mkg/ml), other beta and hemolitic streptococci (groups C, G, F), Streptococcus bovis (group D). Streptococcus viridans.
• gram-negative aerobes: Pseudomonas ѕрр., including G. of aeruginosa, G. of putida, G. of stutzeri, Escherichia coli, Klebsiella ѕрр., including To. pneumoniae, To. oxytoca, To. ozaenae, Enterobacter ѕрр., including E. cloacae, E. aerogenes, E. agglomerans, E. sakazakii, Proteus ѕрр., including G. of mirabilis, G. of vulgaris, Acinetobacter calcoaceticus (including subfamilies of Anitratus, lwoffi), Ayegomopa_ of hydrophila, Capnocytophaga ѕрр., Citrobacter ѕрр., including S. of diversus, S. of freundii, Campylobacter jejuni, Gardnerella vaginalis, Haemophilus ducreyi, N. influenzae (including the strains producing β-lactamazu): N of parainfluenzae, Hafnia alvei: Legionella ѕрр., Morganella morganii, Moraxella (Branhamella) catarrhalis (including the strains producing beta lactamazu), Neisseria gonorrhoeae (including the strains producing beta lactamazu), N. Meningitidis, Providencia ѕрр. (including G. of rettgeri, G. stuartii), Salmonella ѕрр., Serratia (including S. marcescens, S. liquefaciens), Shigella ѕрр., Yersinia enterocolitica.
• anaerobe bacterias: Bacteroides ѕрр., including V. melaninogenicus and other microorganisms of an oral cavity relating to Bacteroides, Clostridium perfringens, Fusobacterium ѕрр., Mobiluncus ѕрр., Peptostreptococcus ѕрр., Veillonella ѕрр.

The majority of strains of enterococci and staphylococcus, resistant to Methicillinum, rezistentna to the majority of tsefalosporinovy antibiotics, including tsefepy.

Tsefepim is inactive concerning some strains of Xanthomonas (Pseudomonas) maltophilia, Bacteroides fragilis and Clostridium difficile.

Pharmacokinetics. The maximum concentration of drug in a blood plasma at intravenous administration is reached in 0,5 hours, at intramuscular introduction – in 1 hour (a dose of 500 mg) and in 2 hours (a dose of 1 - 2 g).

Average therapeutic concentration of a tsefepim in a blood plasma at adult healthy men through different time after single intravenous (in/in) and intramuscular introduction (in oil) are given in table 4.

Average concentration of Tsefepim in plasma (mkg/ml) Table 4.

Tsefepim's dose	0,5 h	1 h	2 h	4 h	8 h	12 h
500 mg in/in	38,2	21,6	11,6	5,0	1,4	0,2
1 g in/in	78,7	44,5	24,3	10,5	2,4	0,6
2 g in/in	163,1	85,8	44,8	19,2	3,9	1,1
500 mg in oil	8,2	12,5	12,0	6,9	1,9	0,7
1 in oil	14,8	25,9	26,3	16,0	4,5	1,4
2 in oil	36,1	49,9	51,3	31,5	8,7	2,3

Linkng of a tsefepim with proteins of plasma makes less than 19% and does not depend on concentration of drug in blood serum. Badly gets through the unimpaired blood-brain barrier. But at an inflammation of a meninx it is found in therapeutic concentration in cerebrospinal fluid.

Considerable concentration are defined in urine, bile, peritoneal liquid, a bronchial secret, tissues of a gall bladder, an appendix and prostate. Distribution volume – 0,25 l/kg, at children aged from 2 months up to 16 years is 0,33 l/kg. Tsefepim is metabolized in N-metilpirolidin which quickly turns into N-metilpirolidina oxide. The average general clearance – 120 ml/min. Tsefepim is distinguished with kidneys, mainly by glomerular filtering. The average renal clearance makes 110 ml/min. In urine about 85% of the entered dose in not changed state, are defined by 1% of N-metilpirolidina, about 6,8% of N-metilpirolidina oxide and about 2,5% of an epimer of Tsefepim. The elimination half-life averages about 2 hours. At the volunteers receiving doses to 2 g intravenously with an interval of 8 hours for 9 days cumulation of drug in an organism was not observed.

For patients 65 years with normal function of kidneys unnecessary are more senior than correction of a dose of Tsefepim, despite the smaller size of renal clearance in comparison with that at young patients.

At patients with renal failures the elimination half-life increases. The elimination half-life of a tsefepim when carrying out a hemodialysis averages 13 hours, when carrying out peritoneal dialysis – 19 hours.

Tsefepim's pharmacokinetics at patients with abnormal liver functions is not changed. Correction of a dose it is not necessary for such patients.

Indications to use:

The infections caused by microorganisms, sensitive to drug:

Adults:

• lower respiratory tract infections,
• intraabdominal infections (including peritonitis and infections of biliary tract,
• infections of skin and hypodermic cellulose,
• febrile neutropenia,

Children:

• pneumonia,
• infections of urinary tract (including pyelonephritis),
• infections of skin and hypodermic cellulose,
• febrile neutropenia.

Route of administration and doses:

Drug is intended for parenteral administration. Before introduction it is recommended to carry out skin test on portability. The dose of drug is established individually depending on severity of a disease, age of the patient, localization of an infection, function of kidneys.

Usual dosing for adults and children with body weight more than 40 kg makes 1 g intravenously or intramusculary each 12 hours. The usual duration of treatment makes 7 - 10 days. Heavy infections can demand more prolonged treatment. Recommendations concerning dosing a tsefep_ma for adults are provided in table 1.

Table 1.

_nfektion easy and moderate severity	500 mg - 1 g in/in or in oil	each 12 h
Heavy infections	2 g in/in	each 12 h
Infections, life-threatening	2 g in/in	each 8 h

For children aged from 2 months the maximum dose should not exceed the recommended dose for adults. The usual recommended dose for children with body weight to 40 kg at the complicated or uncomplicated infections of urinary tract (including pyelonephritis), uncomplicated infections of skin and soft tissues, pneumonia, and also in case of empirical treatment of a febrile neutropenia makes 50 mg/kg of body weight each 12 hours.

The patient with a febrile neutropenia drug each 8 hours appoint in a dose 50 mg/kg of body weight.

For patients 65 years with normal function of kidneys unnecessary are more senior than correction of a dose of a tsefepim, despite the smaller size of renal clearance in comparison with that at young patients.

Correction of the mode of a drug dosing is necessary for patients with a renal failure (clearance of creatinine less than 30 ml/min.). The initial dose has to be same, as well as for patients with normal function of kidneys. Maintenance doses of a tsefepim are given in table 2.

Table 2.

Clearance of creatinine (ml / хв)	Maintenance doses which are recommended
> 50	The usual dosage adequate to weight of an infection (see table 1), the correcting of a dose is not necessary
	2 g everyone 8 h	2 g everyone 12 h	1 g everyone 12 h	500 mg each 12 h
30 - 50	Dose correcting according to clearance of creatinine
	2 g everyone 12 h	2 g everyone 24 h	1 g everyone 24 h	500 mg everyone 24 h
11 - 29	2 g everyone 24 h	1 g everyone 24 h	500 mg each  24 h	500 mg everyone 24 h
<10	1 g everyone 24 h	500 mg each 24 h	250 mg each 24 h	250 mg everyone 24 h
Hemodialysis	500 mg each 24 h	500 mg each 24 h	500 mg each 24 h	500 mg everyone 24 h

If only concentration of creatinine in blood serum is known, then the clearance of creatinine can be determined by the formula given below.

Men. Clearance of creatinine (ml/min.) = the Body weight (kg) × (140 - age) / 72 × creatinine of serum (mg/dl)

Women. Clearance of creatinine (ml/min.) = above-stated value x 0,85

At a hemodialysis for 3 h about 68% of total quantity of a tsefepim are brought out of an organism. At the end of each session it is necessary to enter the repeated dose equal to initial. At continuous peritoneal dialysis drug can be used in the recommended doses, that is 500 mg, 1 g or 2 g depending on weight of an infection with an interval between introductions of a single dose of 48 hours.

Reduction of a dose or increase in an interval between introductions is recommended to children with renal failures.

The pharmacokinetics of a tsefepim at patients with abnormal liver functions is not changed. Correction of a dose for such patients is not necessary.

Administration of drug. Tsefepim it is possible to enter intravenously or by means of a deep intramuscular injection into big muscle bulk (for example in an upper outside quadrant of a gluteus).

Intravenous administration. The intravenous way of introduction is preferable to patients with heavy or life-threatening infections.

At an intravenous way of introduction by tsefepy dissolve in 5 ml or 10 ml of sterile water for injections, in 5% glucose solution for injections or 0,9% chloride sodium solution as it is specified in table 3. Enter intravenously, slowly, within 3 - 5 minutes or through system for intravenous administration.

Intramuscular introduction. Tsefepim it is possible to dissolve in sterile water for injections, 0,9% chloride sodium solution for injections, 5% glucose solution for injections, bacteriostatic water for injections with paraben or benzyl alcohol, 0,5% or 1% hydrochloride lidocaine solution in concentration which are given in table 3.

Table 3.

	Solution volume for cultivation (ml)	The approximate volume of the received solution (ml)	Approximate concentration of Tsefepim (mg/ml)
Intravenous administration 1 g / bottle	10	11,4	90
Intramuscular introduction 1 g / bottle	3	4,4	230

In case of use of lidocaine it is necessary to carry out skin test on portability of local anesthetics.

Ready solution of a tsefepim before introduction should be checked for lack of mechanical inclusions visually.

Features of use:

Use during pregnancy or feeding by a breast. Adequate and well controlled researches at pregnant women were not conducted therefore it is only possible to appoint tsefepy during pregnancy when the expected advantage for mother exceeds potential risk for a fruit.

Tsefepim gets into breast milk in very small amount therefore during treatment by drug feeding by a breast should be stopped.

Children. Drug is used in pediatric practice for treatment of children aged from 2 months.

Features of use. Before introduction it is necessary to carry out skin test on portability.

At prolonged treatment it is regularly necessary to control functional indicators of a liver, kidneys and bodies of a hemogenesis.

Patients with high risk of heavy infections (for example, at the patients who had in the anamnesis transplantation of marrow at its reduced activity happening against the background of malignant hemolitic pathology to the heavy progressing neutropenia) can have an insufficient therefore complex antimicrobic therapy is shown monotherapy.

For patients 65 years with normal function of kidneys unnecessary are more senior than correction of a dose of Tsefepim, despite the smaller size of renal clearance in comparison with that at young patients.

At patients with a renal failure the dose of drug has to be modified depending on degree of manifestation of a renal failure (reduction of a dosage and/or increase in an interval between administrations of drug (see the section "Route of Administration and Doses").

The pharmacokinetics of a tsefepim at patients with abnormal liver functions is not changed. Correction of a dose it is not necessary for such patients.

It is necessary to use with care drug to patients with the burdened allergological anamnesis, and also to patients with the known hypersensitivity to a beta laktamnym to antibiotics as there is a risk of development of cross allergic reactions. In case of allergic reactions it is necessary to stop immediately treatment by drug.

Heavy reactions of hypersensitivity can demand use of adrenaline, a hydrocortisone, antihistaminic drugs and other means of acute management.

Antibiotics of a broad spectrum of activity, especially at long use, can cause pseudomembranous colitis therefore it is necessary to pay attention to developing of diarrhea during treatment tsefepimy. Easy forms of colitis can independently pass after the end of therapy, moderate or serious conditions can demand special treatment.

As well as concerning other antibiotics, prolonged use of a tsefepim can lead to colonization by insensitive microflora. At development of superinfections during treatment use of the relevant activities is necessary.

During treatment by drug detection of false positive reaction of Koombs, and also lozhnopozitivny the test for availability of glucose in urine is possible.

Ability to influence speed of response at control of motor transport or work with other mechanisms. For treatment it is necessary to abstain from driving or work with other mechanisms.

It is impossible to mix tsefepy with other medicines. To apply the solvents listed in the section "Route of Administration and Doses".

Side effects:

With a frequency from 0,1% to 1%:

- hypersensitivity: itch, urticaria,

- from a digestive tract: nausea, vomiting, candidiasis of an oral cavity, diarrhea, colitis (including pseudomembranous (see the section "Features of Use"),

- from the central nervous system: headache,

- others: fever, vaginitis, erythema.

With a frequency from 0,05% to 0,1%: abdominal pain, lock, vazodilatation, disorders of breath, dizziness, paresthesia, genital itch, fever and candidiasis.

With a frequency less than 0,05% the anaphylaxis and epileptoformny attacks were observed.

Local reactions in a drug injection site: at intravenous – phlebitis and an inflammation, at intramuscular – pain, an inflammation.

Poslemarketinogovy researches: encephalopathies (loss of consciousness, hallucinations, stupor, coma), epileptoformny attacks, myoclonia, renal failure, anaphylaxis, including acute anaphylaxis, tranzitorny leukopenia, neutropenia, agranulocytosis and thrombocytopenia.

Laboratory indicators: increase in level of alaninaminotranspherase, aspartate aminotransferase, an alkaline phosphatase, the general bilirubin, anemia, an eosinophilia, increase in a prothrombin time or partial trombolastinovy time (PTT) and a positive take of the test of Koombs without hemolysis. Temporary increase in an urea nitrogen of blood and/or creatinine of serum and tranzitorny thrombocytopenia were noted in less than 0,5% of patients. Also the tranzitorny leukopenia and a neutropenia were noted.

Interaction with other medicines:

Tsefepim concentration from 1 to 40 mg/ml is compatible to such parenteral solutions: 0,9% chloride sodium solution for injections, 5 and 10% glucose solution for injections, lactate sodium solution 6M for injections: solution of 5% of glucose and 0,9% of sodium of chloride for injections, Ringer's solution with a lactate and 5% glucose solution for injections.

To avoid possible medicinal interaction it is not necessary to administer at the same time the drug with solutions of metronidazole, Vancomycinum, gentamycin, Tobramycinum of sulfate and a netilmitsin of sulfate. In case of combined use with the specified drugs it is necessary to enter each antibiotic separately.

Diuretics and aminoglycosides reduce canalicular secretion of a tsefepim and increase its concentration in blood serum, extend an elimination half-life, increase nephrotoxicity and increase risk of development to a nefronekroz. At simultaneous use of a tsefepim and aminoglycosides the risk of ototoksichesky action of the last increases.

Contraindications:

Hypersensitivity to components of drug or cephalosporins, penicillin and another beta лактамным to antibiotics.

Overdose:

Symptoms: in cases of considerable exceeding of the recommended doses, especially at patients with an impaired renal function manifestations of side effect amplify. Symptoms of overdose include the encephalopathy which is followed by hallucinations, consciousness disturbance, a stupor, a coma, a myoclonia, epileptoformny attacks, neuromuscular irritability.

Treatment. It is necessary to stop administration of drug, to carry out symptomatic therapy. Use of a hemodialysis accelerates removal of a tsefepim from an organism, peritoneal dialysis is ineffective. Heavy allergic reactions of immediate type demand use of adrenaline and other forms of an intensive care.

Storage conditions:

Period of validity - 2 years. The prepared solution should be applied at once. To store in the dry, protected from light place at a temperature not over 25 ºС. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

On 1 g of drug in a bottle. On 1 bottle in a cardboard box.