Максипим®

General characteristics. Structure:

Active ingredient: 500 mg, 1 g or 2 g of a tsefepim in the form of a tsefepim of a hydrochloride of monohydrate.

Excipients: L-arginine.

Pharmacological properties:

Pharmacodynamics. Tsefipim possesses a broad spectrum of activity concerning various gram-positive and gram-negative bacteria, including strains, resistant to aminoglycosides or tsefalosporinovy antibiotics of the third generation, such as цефтазидин. Tsefepim is highly steady against hydrolysis by the majority beta лактамаз, has small affinity concerning the beta laktamaz coded by chromosomal genes and quickly gets into gram-negative bacterial cells.

MAKSIPIM is active concerning a wide range of microorganisms. The ratio of MBK / MPK for a tsefepim more than for 80% of isolates of all tested gram-positive and gram-negative microorganisms made = <2. Existence of sinergidny action in relation to aminoglycosides in tests of in vitro was shown.

MAKSIPIM is active concerning the following microorganisms.

Gram-positive aerobes: Staphylococcus aureus (including the strains producing beta lactamazu); Staphylococcus epidermidis (including the strains producing beta lactamazu); other strains of stafilokokk, including S. hominis, S. saprophyticus; Streptococcus pyogenes (group A streptococci); Streptococcus agalactiae (group B streptococci); Streptococcus pneumoniae (including strains with average penicillin resistance - MPK from 0,1 to 1 mkg/ml); other beta and hemolitic streptococci (C, G groups, F), S. bovis (group D), Viridans group streptococci. (The majority of strains of enterococci, for example Enterococcus faecalis, and staphylococcus, resistant to Methicillinum, rezistentna to the majority of tsefalosporinovy antibiotics, including tsefepy).

Gram-negative aerobes: Pseudomonas sp., including P. aeruginosa, P. putida, P. stutzeri; Escherichia coli Klebsiella sp., including K. pneumoniae, K. oxytoca, K. oxaenae; Enterobacter sp., including E. cloacae, E. aerogenes, E. agglomerans, E. sakazakii; Proteus sp., including P. mirabilis, P. vulgaris; Acinetobacter calcoaceticus (subsp. anitratus, lwoffi); Aeromonas hydrophila; Capnocytophaga sp.; Citrobacter sp., including C. diversus, C. freundii; Campylobacter jejuni; Cardnerella vaginalis; Haemophilus ducreyi; Haemophilus influenzae (including the strains producing beta lactamazu); Haemophilus parainfluenzae; Hafnia alvei; Legionella sp.; Morganella morganii; Moraxella cacarrhalis (Branhamella catarrhalis) (including the strains producing beta lactamazu); Neisseria gonorrhoeae (including the strains producing beta lactamazu); Neisseria meningitidis; Providencia sp. (including P. retigeri, P. stuartii); Salmonella sp.; Serratia (including S. marcescens, S. liquefaciens); Shigella sp.; Yersinia enterocolitica.

(Tsefepim is inactive concerning some strains of Xanthmonas maltophilia [Pseudomonas maltophilia]).

Anaerobe bacterias: Bacteroides sp., including B. melaninogenicus and other microorganisms of an oral cavity relating to Bacteroides; Clostridium perfringens; Fusobacterium sp.; Mobiluncus sp.; Peptostreptococcus sp.; Veillonella sp. (Tsefepim is inactive concerning Bacteroides fragilis and Clostridium difficile).

Pharmacokinetics. Average concentration of a tsefepim in a blood plasma at adult healthy men in various terms after single thirty-minute injection of doses of 500 mg, 1 g and 2 g are given below to the table.

Average concentration of a tsefepim in plasma (mkg/ml).

In urine, bile, peritonalny liquid, bubble liquid, a mucous secret of bronchial tubes, a phlegm, a prostate, an appendix and a gall bladder therapeutic concentration of a tsefepim are also reached.

The elimination half-life of a tsefepim from an organism averages about 2 hours. At the healthy people receiving doses to 2 g intravenously with an interval of 8 hours for 9 days cumulation of drug in an organism was not observed.

The average general clearance makes 120 ml/min. Tsefepim is allocated almost only for the account of renal mechanisms of regulation, mainly by glomerular filtering (the average renal clearance makes 110 ml/min.). In urine about 85% of the entered dose in the form of not changed tsefepim are found. Linkng of a tsefepim with plasma proteins makes less than 19% and does not depend on concentration of drug in blood serum.

At patients 65 years with normal function of kidneys are more senior correction of a dose of drug MAKSIPIM, despite the smaller size of renal clearance in comparison with young patients is not required.

The researches conducted on patients with various degree of a renal failure showed increase in biological half-life. On average the elimination half-life at the patients with heavy renal failures demanding treatment by dialysis makes 13 hours for a hemodialysis and 19 hours for peritonalny dialysis.

At patients with abnormal function of kidneys the dose has to be selected individually (see the section Route of administration and doses).

The pharmacokinetics of a tsefepim at patients with the broken function of a liver or a mucoviscidosis is not changed. Correction of a dose for such patients is not required.

Children. Assessment of pharmacokinetics of a tsefepim was carried out at children aged from 2 months up to 11 years after single administration or introduction of several doses of drug by each 8 hours (n=29) and each 12 hours (n=13). After a single intravenous injection the general clearance and distribution volume in steady state 3,3 (± 1,0) ml/min. and 0,3 (± 0,1) on average made l/kg of an organism, respectively. Allocation of a tsefepim in an invariable view with urine made 60,4 (± 30,4) % of the entered dose, and average renal clearance 2,0 (± 1,1) ml/min. The age and a sex of patients (25 boys and 17 girls) had no significant effect on the general clearance from an organism and distribution volume taking into account the amendment on the body weight of everyone.

ри introduction of a tsefepim in a dose of 50 mg/kg it was not celebrated each 12 hours (n=13) of cumulation of drug while Cmax, the area under curve AUC and t1/2 increased approximately by 15% in steady state at introduction according to the scheme of 50 mg/kg each 8 hours. Exposure of a tsefepim at children after intravenous administration in a dose of 50 mg/kg is comparable with exposure at adults after an intravenous dose of 2 g. Absolute bioavailability of a tsefepim at eight patients after an intramuscular injection in a dose of 50 mg/kg made 82,3 (± 15) %.

Indications to use:

• The infectious diseases caused by microorganisms, sensitive to drug.
• Lower respiratory tract infections, including pneumonia and bronchitis.
• The infections of uric ways as complicated, for example pyelonephritis, and uncomplicated.
• Infections of skin and skin structures.
• Intraabdominal infections, including peritonitis and infections of bilious ways.
• Gynecologic infections.
• Septicaemia.
• Empirical treatment at a febrile neutropenia.

For identification of a microorganism activator (activators) and definition of sensitivity to a tsefepim it is necessary to carry out the corresponding tests. However, MAKSIPIM can be applied in the form of monotherapy even before identification of a microorganism of the activator as possesses a wide range of antibacterial action concerning gram-positive and gram-negative microorganisms. At patients with risk mixed аэробно / anaerobic (including Bacterioides fragilis) the infection before identification of the activator can begin treatment with drug MAKSIPIM in a combination with the drug influencing on anaerobe bacterias.

Route of administration and doses:

Doses and way of introduction vary depending on sensitivity of microorganisms of activators, weight of an infection, and also a condition of function of kidneys at the patient.

Adult:

To children (from 2 months to 16 years). The maximum dose for children should not exceed the recommended dose for adults. The usual recommended dose to children with body weight to 40 kg at the complicated or uncomplicated infections of uric ways (including pyelonephritis), uncomplicated infections of skin and skin structures, pneumonia, and also at empirical treatment of neytropenichesky fever makes 50 mg/kg each 12 hours (the patient with neytropenichesky fever each 8 hours).

The usual duration of treatment makes 7-10 days; heavy infections can demand more long treatment.

Renal failure. At patients with renal failures (creatinine clearance <30 ml/min.), a dose of drug MAKSIPIM it has to be corrected. The initial dose of drug MAKSIPIM has to be same, as well as for patients with normal function of kidneys. The recommended maintenance doses of a tsefepim are presented in the table.

When there are only data on stationary concentration of creatinine of serum, it is possible to use the following formula for determination of clearance of creatinine:

Men: Creatinine clearance (ml/min.) =

the weight (kg) x 140 - age 72 x creatinine of serum (mg/dl)

Women: above-stated value x 0,85

At the patients who are on a hemodialysis in 3 hours is removed from an organism about 68% of total quantity of a tsefepim. At the end of each session of dialysis it is necessary to enter the repeated dose equal to an initial dose. At the patients who are on continuous out-patient peritonalny dialysis tsefepy it is possible to use in the initial normal recommended doses, i.e. 500 mg, 1 g or 2 g depending on weight of an infection, and the interval between doses makes 48 hours.

Data on use of drug for children with an impaired renal function are absent. As the pharmacokinetics of a tsefepim at adults and children has similar character (see PHARMACOKINETICS), the same changes of the dose mode, as well as the adult are recommended to children with an impaired renal function.

MAKSIPIM can be entered intravenously or by means of a deep intramuscular injection, into big muscle bulk (for example, into an upper, external quadrant of a gluteus).

Intravenous administration. The intravenous way of introduction is preferable to patients with heavy or life-threatening infections, especially at threat of shock.

For intravenous administration of MAKSIPIM dissolve in 5 or 10 ml of sterile water for injections, 5% glucose solution for injections or 0,9% chloride sodium solution as it is specified in the table given below, enter intravenously within 3-5 minutes. For introduction through system for intravenous injection the prepared solution is combined with other solutions for intravenous injections and entered within not less than 30 minutes. Drug MAKSIPIM solutions in concentration from 1 to 40 mg/ml are compatible to the following parenteral solutions: 0,9% chloride sodium solution for injections; 5% or 10% glucose solutions for injections; M/6 lactate sodium solution for injections, solution of 5% of glucose and 0,9% of sodium of chloride for injections; Ringer's solution with a lactate and 5% dextrose solution for injections.

In order to avoid possible medicinal interaction with other drugs, drug MAKSIPIM solutions (as well as most of others beta лактамных antibiotics) should not be entered along with solutions of metronidazole, Vancomycinum, gentamycin, Tobramycinum of sulfate and a netilmitsin of sulfate. At purpose of drug MAKSIPIM with the listed drugs it is necessary to enter each antibiotic separately.

Intramuscular introduction. MAKSIPIM 5% glucose solution for injections or 0,9% chloride sodium solution for injections, bacteriostatic water for injections with paraben or benzyl alcohol dissolve in sterile water for injections, 0,5% or 1% hydrochloride lidocaine solution, as shown below the table.

As well as other parenteral medicines, the prepared drug solutions before introduction have to be checked for lack of mechanical inclusions.

At storage powder in a bottle or solution can darken, however it does not influence activity of drug.

Precautionary measures / Preventions. It is necessary to define precisely whether were noted at the patient of reaction of immediate hypersensitivity on tsefepy, cephalosporins, penicillin or others beta лактамные antibiotics earlier. Antibiotics should be applied with care at all patients with any forms of an allergy, especially on medicines. At emergence of allergic reaction use of drug should be stopped. Serious reactions of immediate hypersensitivity can demand use of adrenaline and other forms of the supporting treatment.

When using practically of all antibiotics of a broad spectrum of activity it was reported about cases of pseudomembranous colitis. Therefore it is important to mean this diagnosis in case of developing of diarrhea during treatment by drug MAKSIPIM. Easy forms of colitis can react to the termination of administration of drug; moderate or hard cases can demand special treatment.

As well as in case of other antibiotics, use of drug MAKSIPIM can lead to colonization of insensitive microflora. At development of superinfections during treatment acceptance of the appropriate measures is necessary.

Lactation pregnancy / period. Tests for animals showed lack of impact on reproductive function and any harmful effects on a fruit, however adequate and well controlled tests at pregnant women were not carried out. Drug should be used during pregnancy only under observation of the doctor.

Tsefepim is allocated in female breast milk in very low concentration. However, in the period of a lactation it is necessary to use drug with care.

Use for children. Safety and efficiency of a tsefepim at treatment of the uncomplicated and complicated infections of uric ways (including pyelonephritis), uncomplicated infections of skin and skin structures, pneumonia, and also at empirical treatment of neytropenichesky fever were established for age groups from 2 months to 16 years. Expediency of use of drug MAKSIPIM in these age groups is confirmed by results of adequate and well controlled tests of a tsefepim at adults and the additional data on pharmacokinetics and safety received in pediatric tests (see PHARMACOKINETICS).

Features of use:

For identification of a microorganism activator and definition of sensitivity to a tsefepim it is necessary to carry out the corresponding tests.
At risk mixed аэробно / anaerobic (including Bacterioides fragilis) infections treatment by drug Maksipim in a combination with the drug operating on anaerobe bacterias can be begun before identification of the activator.
At development of heavy allergic reaction during Maksipim's introduction can be required urgent in/in introduction of GKS, antihistaminic, angiotonic drugs, to injection of normal saline solutions and carrying out the measures directed to breath function maintenance.
At emergence of diarrhea against the background of treatment by Maksipim it is necessary to consider a possibility of development of pseudomembranous colitis. Easy forms of colitis can independently pass after the termination of administration of drug; moderate or hard cases can demand special treatment.
At Maksipim's use (as well as other antibiotics) development of superinfection is possible that demands drug withdrawal and purpose of the corresponding treatment.
At simultaneous administration of solution of Maksipim (as well as most of others beta лактамных antibiotics) with solutions of metronidazole, Vancomycinum, gentamycin, Tobramycinum of sulfate and a netilmitsin of sulfate perhaps pharmaceutical interaction. At Maksipim's appointment with the listed drugs it is necessary to enter each antibiotic separately.
Use in pediatrics
 The profile of safety of use of drug for children and at adults is identical.
Safety and efficiency of use of drug for children aged up to 2 months is not established.
Drug is recommended to be used at children from 2 months.

Side effects:

MAKSIPIM is usually well transferred. In clinical tests the frequency of the side effects connected using drug MAKSIPIM was low. Symptoms from digestive tract and reaction of hypersensitivity were the most frequent side effects. The side effects arising with a frequency of 0,3-1% are listed below (exceptions are given in brackets):

• Hypersensitivity: rash (2,8%), itch (1,3%), rise in temperature
• Digestive tract: diarrhea (3,6%), nausea (3%), vomiting (2,3%), lock (1,4%), abdominal pains (1,2%), dyspepsia
• Cardiovascular system: stethalgias, tachycardia
• Respiratory system: cough, pharyngalgia, asthma
• Central nervous system: headaches (3,4%), dizziness, insomnia, paresthesias, concern, confusion of consciousness
• Other: adynamy, perspiration, vaginitis, peripheral hypostases, dorsodynias

Anaphylactic reactions and spasms were noted with a frequency <0,1%.

Local reactions in a point of intravenous injection (phlebitis and an inflammation) were noted at 3,3% of patients. MAKSIPIM at intramuscular introduction was transferred very well, and the inflammation or pains in a point of an injection were observed at only 1,5% of patients.

Rejections of these laboratory analyses: During the clinical tests given below side effects had tranzitorny character and arose with a frequency of £2 of % (exceptions are given in brackets):

raising of alaninaminotranspherase (3,2%), aspartate aminotransferases (2,7%), an alkaline phosphatase, the general bilirubin, anemia, an eosinophilia, increase in a prothrombin time or PTT and a positive take of the test of Koombs without hemolysis (18,3%). Temporary raising of an urea nitrogen of blood and/or creatinine of serum and tranzitorny thrombocytopenia were noted at <0,5% of patients. Also the tranzitorny leukopenia and a neutropenia were noted (<0,5%).

The listed below side effects and the changed data of laboratory analyses were also noted for other antibiotics of a tsefalosporinovy class: a small tortoiseshell, a syndrome Stephens-Johnson, a multiple erythema, a toxic necrolysis of epidermis, colitis, a renal failure, a toxic nephropathy, aplastic anemia, hemolitic anemia, bleeding, spasms, an abnormal liver function, including a cholestasia, and false positive results of analyses on urine glucose.

Interaction with other medicines:

In the researches in vitro an action synergism Maksipim in relation to aminoglycosides was shown.
At simultaneous use of drugs the risk of development of nephrotoxicity and ototoxicity of aminoglikozidny antibiotics increases.

Contraindications:

MAKSIPIM is contraindicated to patients with early reactions to a tsefepim or L-arginine, and also to antibiotics of a tsefalosporinovy class, penicillin or another beta лактамным to antibiotics.

Overdose:

In cases of considerable exceeding of the recommended doses, especially at patients with an impaired renal function, use of dialysis will accelerate removal of a tsefepim from an organism; at the same time the hemodialysis is more preferable than peritonalny dialysis.

Storage conditions:

To store at a temperature not above 30 °C, in the place protected from light. The prepared drug solutions for intramuscular and vnutivenny injections are stable within 24 hours at the room temperature or 7 days at storage in the refrigerator (2-8 °C). To store in the place, unavailable to children. A period of validity - 3 years. Not to use drug after the expiry date specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Bottles on 500 mg, 1 g and 2 g.