Composition, form of production and packaging
Powder for preparation of a solution for iv and in / m introduction white or white with a yellowish shade of color.
cefepime dihydrochloride monohydrate 500 mg
- "- 1 g
Vials (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2008.
Cephalosporin antibiotic IV generation. Has a wide spectrum of action against gram-positive and gram-negative bacteria, strains resistant to aminoglycosides or cephalosporin antibiotics of the third generation. Cefepime is highly resistant to hydrolysis by most ОІ-lactamases, has a low affinity for ОІ-lactamases, encoded by chromosomal genes, and rapidly penetrates into gram-negative bacterial cells.
Maxipim is active against Gram-positive aerobic bacteria: Staphylococcus aureus (including strains producing ОІ-lactamases), Staphylococcus epidermidis (including strains producing ОІ-lactamases), other strains of Staphylococcus spp. (including Staphylococcus hominis, Staphylococcus saprophyticus), Streptococcus pyogenes (Streptococcus group A), Streptococcus agalactiae (Streptococcus group B), Streptococcus pneumoniae (including strains with an average penicillin resistance - MIC of 0.1 to 1 Ојg / ml), Streptococcus bovis (group D), Streptococcus viridans, other beta-hemolytic streptococci (groups C, G, F); Gram-negative aerobic bacteria:Pseudomonas spp. (including Pseudomonas aeruginosa, Pseudomonas putida, Pseudomonas stutzeri), Escherichia coli, Klebsiella spp. (including Klebsiella pneumoniae, Klebsiella oxytoca, Klebsiella ozaenae), Enterobacter spp. (including Enterobacter cloacae, Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter sakazakii), Proteus spp. (including Proteus mirabilis, Proteus vulgaris), Acinetobacter calcoaceticus (subtype Acinetobacter anitratus, Acinetobacter lwoffii), Aeromonas hydrophila, Capnocytophaga spp., Citrobacter spp. (including Citrobacter diversus, Citrobacter freundii), Campylobacter jejuni, Gardnerella vaginalis, Haemophilus ducreyi, Haemophilus influenzae (including strains producing О±-lactamases), Haemophilus parainfluenzae, Hafnia alvei, Legionella spp., Morganella morganii, Moraxella catarrhalis (including strains producing ? -lactamase), Neisseria gonorrhoeae (including strains producing ОІ-lactamases), Neisseria meningitidis, Providencia spp. (including Providencia rettgeri, Providencia stuartii), Salmonella spp., Serratia spp. (including Serratia marcescens, Serratia liquefaciens), Shigella spp., Yersinia enterocolitica; anaerobic bacteria: Bacteroides spp. (including Bacteroides melaninogenicus, other strains of Bacteroides spp. / in the oral cavity), Clostridium perfringens, Fusobacterium spp., Mobiluncus spp., Peptostreptococcus spp., Veillonella spp.
Some strains of Xanthomonas maltophilia (Pseudomonas maltophilia), Bacteroides fragilis, Clostridium difficile are resistant to the drug.
Most strains of enterococci (including Enterococcus faecalis) and staphylococci resistant to methicillin, are resistant to most cephalosporin antibiotics, including cefepime.
The mean concentrations of cefepime in plasma (Ојg / ml) in adult healthy men after a single IV injection for 30 min are shown in Table 1.
The dose of cefepime 0.5 h 2 h 4 h 12 h
500 mg iv 38.2 11.6 5.0 0.2
1 g IV 78.7 24.3 10.5 0.6
2 g i / v 163.1 44.8 19.2 1.1
C max in blood plasma cefepime with iv injection at doses of 500 mg, 1 g and 2 g is 39.1 В± 3.5 Ојg / ml, 81.7 В± 5.1 Ојg / ml and 163.9 В± 25.3 Ојg / ml, respectively.
After the / m introduction cefepime is absorbed completely. At doses of 500 mg, 1 g and 2 g C max of cefepime in blood plasma is respectively 13.9 В± 3.4 Ојg / ml, 29.6 В± 4.4 Ојg / ml, 57.5 В± 9.5 Ојg / ml; T max is 1.4 В± 0.9 h, 1.6 В± 0.4 h, 1.5 В± 0.4 h, respectively. Average concentrations of cefepime in plasma (Ојg / ml) after a single IM are shown in Table 2.
The dose of cefepime 0.5 h 1h 2h 8h
500 mg 8.2 12.5 12.0 1.9
1 g 14.8 25.9 26.3 4.5
2 g 36.1 49.9 51.3 8.7
The binding to plasma proteins is less than 19% and does not depend on the concentration of cefepime in serum.
In healthy people with iv injection of Maxipim in a dose of 2 g with an interval of 8 hours for 9 days, cumulation of cefepime in the body was not observed.
Therapeutic concentrations of cefepime are found in urine, bile, peritoneal fluid, contents of burn blisters, bronchial mucus secretion, prostate tissue, appendix and gallbladder.
Metabolism and excretion
Cefepime is metabolized to N-methylpyrrolidine, which rapidly converts to N-methylpyrrolidine oxide.
The average T 1/2 cefepime is about 2 hours from the body. The total clearance is on average 120 ml / min. Cefepime is excreted almost entirely due to renal regulation mechanisms, mainly by glomerular filtration (mean renal clearance is 110 ml / min). In urine, approximately 85% of the injected cefepime is unchanged, less than 1% of N-methylpyrrolidine, about 6.8% of N-methylpyrrolidine oxide and about 2.5% of cefepime epimer.
Pharmacokinetics in special clinical cases
After a single intravenous administration of the drug at a dose of 1 g, patients over 65 years of age had an increase in AUC and a decrease in renal clearance, compared with young patients.
Patients with impaired renal function require a correction of the dosing regimen. In patients with renal insufficiency of varying severity, T 1/2 is increased from the body. In severe violations of kidney function requiring dialysis sessions, T 1/2 is an average of 13 hours for hemodialysis and 19 hours for peritoneal dialysis.
The pharmacokinetics of cefepime in patients with impaired liver function or cystic fibrosis has not been altered. Correction of dose for such patients is not required.
In children aged 2 months to 11 years after a single IV or IV injection of the drug at a dose of 50 mg / kg body weight and after the administration of several doses of the drug every 8 hours (n = 29) or every 12 hours (n = 13), but not less than 48 hours the total clearance and V d were 3.3 В± 1.0 ml / min / kg and 0.3 В± 0.1 l / kg. The excretion of cefepime unchanged in the urine was 60.4 В± 30.4% of the administered dose, and the renal clearance was 2.0 В± 1.1 ml / min / kg on average. Age and sex of patients did not significantly affect overall clearance and V d , taking into account the correction for body weight of each.
When the drug was administered at a dose of 50 mg / kg every 12 hours (n = 13) cefepime cumulation was not observed, while Cmax , AUC and T1 / 2 were increased by approximately 15% in the steady state when administered in a 50 mg / kg every 8 hours. The pharmacokinetic parameters of cefepime in children after IV injection at a dose of 50 mg / kg are comparable with the pharmacokinetic parameters of the drug in adults after iv introduction at a dose of 2 g.
After the / m administration, C max cefepime in blood plasma averaged 68 Ојg / ml for a median of 0.75 h. 8 hours after the IM, the cefepime concentration in the blood plasma averaged 6 Ојg / ml. Absolute bioavailability of cefepime after a / m injection is on average 82%.
Concentrations of the drug in cerebrospinal fluid (CSF) and in blood plasma in children with bacterial meningitis are presented in Table 3.
Time after administration Concentration in blood plasma (Ојg / ml) * Concentration in CSF (Ојg / ml) * Concentration ratio in CSF / plasma *
0.5 h 67.1 В± 51.2 5.7 В± 0.14 0.12 В± 0.14
1 h 44.1 В± 7.8 4.3 В± 1.5 0.1 В± 0.04
2 h 23.9 В± 12.9 3.6 В± 2.0 0.17 В± 0.09
4 h 11.7 В± 15.7 4.2 В± 1.1 0.87 В± 0.56
8 h 4.9 В± 5.9 3.3 В± 2.8 1.02 В± 0.64
* The age of children from 3.1 months to 12 years with a standard deviation of В± 3 years.
The dose of the drug is 50 mg / kg of body weight with IV infusion for 5-20 minutes every 8 hours. Concentrations in plasma and CSF are determined at the end of infusion for 2 or 3 days of treatment with the drug.
Treatment of infectious-inflammatory diseases caused by microorganisms sensitive to the preparation:
- infections of the lower respiratory tract (including pneumonia and bronchitis);
- urinary tract infections (both complicated, including pyelonephritis, and uncomplicated);
- skin and soft tissue infections;
- intra-abdominal infections (including peritonitis and biliary tract infections);
- gynecological infections;
- Neutropenic fever (as an empirical therapy);
bacterial meningitis in children.
Prevention of infections in the conduct of cavitary surgery.
Treatment with Maxiplex can begin even before the identification of the microorganism of the pathogen.
The dose and route of administration are determined depending on the sensitivity of the pathogen, the severity of the infection, and also on the state of kidney function of the patient.
The IV route is preferred for patients with severe or life-threatening infections.
Adults and children with a body weight of more than 40 kg with normal kidney function the drug is prescribed in the following doses.
Disease severity Single dose Interval between administrations
Urinary tract infections of mild and moderate severity 0.5-1 g IV or IM every 12 h
Other infections of mild to moderate severity 1 g IV or IM every 12 h
Severe infections 2 g IV every 12 h
Very serious and life-threatening infections 2 g IV every 8 h
To prevent possible infections during surgical operations 60 minutes prior to the beginning of the operation, the drug is administered at a dose of 2 g IV for 30 minutes. After the end of the infusion additionally appoint metronidazole IV in a dose of 500 mg. Metronidazole solutions should not be administered concomitantly with Maxipim. Infusion system before the introduction of metronidazole should be washed.
During prolonged (more than 12 hours) surgical operations 12 hours after the first dose, repeated administration of an equal dose of Maxipim is recommended with the subsequent administration of metronidazole.
For children aged 2 months, the maximum dose should not exceed the recommended dose for adults. The average dose for children weighing up to 40 kg with complicated or uncomplicated urinary tract infections (including pyelonephritis), uncomplicated infections of the skin and soft tissues, pneumonia, the empirical treatment of neutropenic fever is 50 mg / kg every 12 hours.
For patients with neutropenic fever and bacterial meningitis, the drug is administered at a dose of 50 mg / kg every 8 hours.
The average duration of therapy is 7-10 days. In severe infections, longer treatment may be required.
In patients with impaired renal function (KK less than 30 ml / min) , correction of the dosing regimen is necessary. The initial dose of Maxipim should be the same as for patients with normal renal function. The maintenance doses of the preparation are determined depending on the values вЂ‹вЂ‹of the SC.
Creatinine clearance (mL / min) Recommended doses
2 g every 8 h 2 g every 12 h 1 g every 12 h 500 mg every 12 h
> 50 recommended dose, no correction needed
50-30 2 g every 12 h 2 g every 24 h 1 g every 24 h 500 mg every 24 h
29-11 2 g every 24 h 1 g every 24 h 500 mg every 24 h 500 mg every 24 h
? 10 1 g every 24 hours 500 mg every 24 hours 250 mg every 24 hours 250 mg every 24 hours
With hemodialysis, approximately 68% of the total amount of cefepime is removed from the body within 3 hours. At the conclusion of each session, a repeat dose equal to the initial dose should be given. In patients who are on continuous outpatient peritoneal dialysis, Maxypem can be used in average recommended doses, i.Рµ.500 mg, 1 g or 2 g, depending on the severity of the infection, with an interval between single dose administration of 48 hours.
In children with impaired renal function, the same changes in the dosing regimen are recommended, as for adults, according to the table above.
Rules for the preparation and administration of solutions
To prepare the solution for intravenous administration, the powder for injection in the vial is dissolved in 5 ml or 10 ml of sterile water for injection, 5% glucose solution or 0.9% sodium chloride solution, as indicated in the table below. Intramuscularly Maxipim is injected for 3-5 minutes. For administration through the IV infusion system, the prepared solution is combined with other solutions for IV infusions and administered for at least 30 minutes.
Solutions Maxipim in a concentration of 1 to 40 mg / ml are compatible with the following solutions for parenteral administration: 0.9% solution of sodium chloride for injection, 5% or 10% solutions of glucose for injection, M / 6 solution of sodium lactate for injection, solution of 5% glucose and 0.9% sodium chloride for injection, Ringer's solution with lactate and 5% glucose solution for injection.
To prepare a solution for intravenous injection, the powder for injections in the vial is dissolved in sterile water for injection, 5% glucose solution for injection or 0.9% solution of sodium chloride for injection, bacteriostatic water for injection with paraben or benzyl alcohol, 0.5% or 1 % solution of lidocaine hydrochloride, as indicated in the table.
Powder for Injection Volume of dilution pore ( ml) Volume of obtained r-ra (ml) Concentration of cefepime (mg / ml)
500 mg / fl. 5 5.6 100
1 g / l. 10 11.3 100
500 mg / fl. 1.3 1.8 280
1 g / l. 2.4 3.6 280
When stored, the powder in the vial or solution may darken, but this does not affect the activity of the drug.
On the part of the digestive system: 1.2% - diarrhea; > 0.1-1% - nausea, vomiting, colitis (including pseudomembranous colitis); 0.05-0.1% - abdominal pain, constipation, taste change.
Allergic reactions: 1.8% - rash; > 0.1-1% - itching, hives; less than 0.05% - anaphylactic reactions.
From the central nervous system and peripheral nervous system: > 0.1-1% - headaches; 0.05-0.1% - dizziness, paresthesia; less than 0.05% - convulsions.
Dermatological reactions: 0.05-0.1% - redness of the skin. The most common in children is a rash.
On the part of the hematopoiesis system :? 2% - anemia.
On the part of the indicators of laboratory studies: 3.2% - increase in ALT, 2.7% - increase in AST; ? 2% - increase in AP, increased total bilirubin, eosinophilia, increased prothrombin time or partial thromboplastin time; <0.5% - temporary increase of blood urea nitrogen and / or serum creatinine, transient thrombocytopenia, transient leukopenia and neutropenia; 18.3% - positive result of Coombs test without hemolysis.
Local reactions: 5.2% - with intravenous administration (2.9% - phlebitis, 0.1% - inflammation); 2.6% - inflammation or pain with the / m injections.
Other: > 0.1-1% - fever, vaginitis, erythema; 0.05-0.1% - shortness of breath, chills, genital itching, candidiasis.
Maksipim usually well tolerated. In clinical trials, the incidence of side effects associated with the use of the drug was low. The most frequent side effects were the symptoms of the digestive system and allergic reactions.
When using other antibiotics, the group of cephalosporins: hives, Stevens-Johnson syndrome, multiple erythema, toxic necrolysis of the epidermis, colitis, renal dysfunction, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhage, convulsions, impaired liver function, including cholestasis, and false positive results of tests for urine glucose.
- Hypersensitivity to cefepime or L-arginine, as well as to cephalosporin antibiotics, penicillins or other beta-lactam antibiotics.
PREGNANCY AND LACTATION
Adequate and strictly controlled studies of the safety of Maxipim in pregnancy have not been conducted; The use of the drug is possible only under the supervision of a doctor.
Cefepime is excreted in breast milk in very low concentrations. The use of the drug during lactation (breastfeeding) is possible in the event that the intended benefit to the mother exceeds the potential risk for the infant.
In experimental studies on laboratory animals, there was no effect on reproductive function and any fetotoxic effect of cefepime.
APPLICATION FOR FUNCTIONS OF THE LIVER
In patients with impaired renal function (KK less than 30 ml / min) , correction of the dosing regimen is necessary.
To identify the microorganism-pathogen and determine sensitivity to cefepime, appropriate tests should be carried out.
At the risk of mixed aerobic / anaerobic (including Bacterioides fragilis) infections, treatment with Maxipim in combination with a drug acting on anaerobes can begin before identification of the pathogen.
With the development of a severe allergic reaction during Maxipim administration, it may be necessary to take an urgent IV injection of SCS, antihistamines, vasopressor preparations, intravenous infusion of physiological solutions, and measures aimed at maintaining the function of respiration.
When diarrhea occurs against the background of Maxiphic treatment, the possibility of developing pseudomembranous colitis should be considered. Light forms of colitis can pass by itself after stopping the drug; mild or severe cases may require special treatment.
When using Maxipim (as well as other antibiotics), it is possible to develop superinfection, which requires withdrawal of the drug and the appointment of appropriate treatment.
With the simultaneous administration of Maxipim's solution (like most other beta-lactam antibiotics) with solutions of metronidazole, vancomycin, gentamicin, tobramycin sulfate and netilmicin sulfate, a pharmaceutical interaction is possible. When appointing Maxipim with the listed drugs, each antibiotic should be administered separately.
Use in Pediatrics
The safety profile of the drug in children and adults is the same.
Safety and efficacy of the drug in children under 2 months of age have not been established.
The drug is recommended for use in children from 2 months .
Symptoms: a significant overdose describes the symptoms of encephalopathy.
Treatment: in cases of significant excess of recommended doses, especially in patients with impaired renal function, hemodialysis is indicated.
In vitro studies the synergy of Maxipim action with respect to aminoglycosides was shown.
With the simultaneous use of drugs, the risk of developing nephrotoxicity and ototoxicity of aminoglycoside antibiotics is increasing.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of the reach of children, protected from light, at a temperature of no higher than 30 В° C. Shelf life - 3 years.
The prepared solutions of the drug for intravenous and / or intramuscular administration are stable for 24 hours at room temperature or 7 days when stored in a refrigerator (2-8 В° C).