INSTRUCTIONSONUSE

GIOSEF

GIOCEF

Trade name of the drug: Giosef

Active ingredients (INN):cefepime hydrochloride, tazobactam sodium

Dosage form:powder for injection solution

	Composition: 1 bottle/ampoule		Quantity of bottle/ampoules
		1.125 g/fl		1,250 g/fl	1.50 g/fl
Cefepime hydrochloride in terms of cefepime		1.0 g		1.0 g	1.0 g
Tazobactam sodium in terms of tazobactam		0.125 g		0.250 g	0.500 g
Water for injection		10.0 ml		10.0 ml	10.0 ml

Description:almost white or cream-colored powder.

Pharmacotherapeutic group:antibiotic (group of cephalosporins)

ATC code: J01DA24; J01CG02

Pharmacological properties

Zhiosef has a wide spectrum of action against various gram-positive and gram-negative bacteria, including strains resistant to aminoglycosides or third-generation cephalosporin antibiotics such as ceftazidine. Cefepime is highly resistant to hydrolysis by most beta-lactamases, has low affinity for beta-lactamases encoded by chromosomal genes, and quickly penetrates into gram-negative bacterial cells.

Zhiosef is active against a wide range of microorganisms. The MBC/MIC ratio for cefepime for more than 80% of the isolates of all tested gram-positive and gram-negative microorganisms was =<2. It has been demonstrated to have a synergistic effect with aminoglycosides inin vitrotests.

Zhiosef is active against the following microorganisms:

Gram-positive aerobes:Staphylococcus aureus (including beta-lactamase-producing strains); Staphylococcus epidermidis (including beta-lactamase-producing strains); other strains of staphylococci, includingS. hominis, S. saprophyticus; Streptococcus pyogenes(group A streptococci); Streptococcus agalactiae (group B streptococci); Streptococcus pneumoniae(including strains with intermediate resistance to penicillin — MIC from 0.1to 1 μg/ml) ; other beta-hemolytic streptococci (groups C, G, F),S. bovis (group D), streptococci of the Viridans group. (Most strains of enterococci, such as Enterococcus faecalisand methicillin-resistant staphylococci, are resistant to most cephalosporin antibiotics, including cefepime.)

Gram-negative aerobes:Pseudomonas sp., including P . aeruginosa, P. putida, P. stutzeri; Escherichia coli Klebsiellasp., includingK. pneumoniae, K. oxytoca, K. oxaenae; Enterobactersp., includingE. cloacae, E. aerogenes, E. agglomerans, E. sakazakii; Proteussp., includingP. mirabilis, P. vulgaris; Acinetobacter calcoaceticus (subsp. anitratus, lwoffi); Aeromonas hydrophila; Capnocytophagasp.; Citrobacter sp., includingC. diversus, C. freundii; Campylobacter jejuni; Cardnerella vaginalis; Haemophilus ducreyi; Haemophilus influenzae(including beta-lactamase producing strains); Haemophilus parainfluenzae; Hafnia alvei; Legionellasp.; Morganella morganii; Moraxella cacarrhalis(Branhamella catarrhalis)(including beta-lactamase producing strains ); Neisseria gonorrhoeae(including beta-lactamase producing strains); Neisseria meningitidis; Providenciasp. (includingP. retigeri, P. stuartii);Salmonellasp.; Serratia(including S. marcescens, S. liquefaciens); Shigellasp.; Yersinia enterocolitica.

(Cefepime is inactive against some strains of Xanthmonas maltophilia[Pseudomonas maltophilia]).

Anaerobes: Bacteroidessp., includingB. melaninogenicusand other microorganisms of the oral cavity belonging toBacteroides; Clostridium perfringens; Fusobacteriumsp.; Mobiluncussp.; Peptostreptococcussp.; Veillonellasp.

Pharmacokinetics

The mean plasma concentrations of cefepime in adult healthy men at various times after a single thirty-minute infusion of doses of 500 mg, 1 g and 2 g are shown in the table below.

Mean plasma concentrations of cefepime (µg/ml)

Cefepime dose	0.5 h	1 h	2 hours	4 h	8 h	12 h
500 mg IV	38.2	21.6	11.6	5.0	1,4	0.2
1 g IV	78.7	44.5	24.3	10.5	2,4	0.6
2 g IV	163.1	85.8	44.8	19.2	3.9	1,1
500 mg IM	8.2	12.5	12.0	6.9	1.9	0.7
1 g i/m	14.8	25.9	26.3	16.0	4.5	1,4
2 g i/m	36.1	49.9	51.3	31.5	8.7	2,3

In urine, bile, peritoneal fluid, bladder fluid, bronchial mucous secretions, sputum, prostate, appendix and gall bladder, therapeutic concentrations of cefepime are also achieved.

On average, the half-life of cefepime from the body is about 2 hours. In healthy people who received doses of up to 2 g intravenously at intervals of 8 hours for 9 days, no accumulation of the drug in the body was observed.

The average total clearance is 120 ml/min. Cefepime is excreted almost exclusively through renal regulatory mechanisms, mainly by glomerular filtration (average renal clearance is 110 ml/min). Approximately 85% of the administered dose is found in urine as unchanged cefepime. The binding of cefepime to plasma proteins is less than 19% and does not depend on the concentration of the drug in the blood serum.

In patients over 65 years of age with normal renal function, no dose adjustment of Zhiosef is required, despite the lower renal clearance compared to young patients.

Studies conducted on patients with varying degrees of renal failure have demonstrated an increase in the half-life from the body. The average elimination half-life in patients with severe renal impairment requiring dialysis treatment is 13 hours for hemodialysis and 19 hours for peritoneal dialysis.

In patients with abnormal renal function, the dose should be selected individually (see DOSAGE AND ADMINISTRATION section).

The pharmacokinetics of cefepime in patients with impaired liver function or cystic fibrosis is not changed. No dose adjustment is required for such patients.

Children. The pharmacokinetics of cefepime were assessed in children aged 2 months to 11 years after a single administration or administration of several doses of the drug every 8 hours (n=29) and every 12 hours (n=13). After a single intravenous injection, total body clearance and volume of distribution at steady state averaged 3.3 (±1.0) ml/min/kg and 0.3 (±0.1) L/kg, respectively. Excretion of unchanged cefepime in urine was 60.4 (±30.4)% of the administered dose, and the average renal clearance was 2.0 (±1.1) ml/min/kg. The age and gender of the patients (25 boys and 17 girls) did not have a significant effect on the total body clearance and volume of distribution when adjusted for body weight. When cefepime was administered at a dose of 50 mg/kg every 12 hours (n=13), no accumulation of the drug was observed, while C_max, area under the AUC curve and t_1/2 sub> increased by approximately 15% at steady state when administered at a 50 mg/kg schedule every 8 hours. Exposure of cefepime in children after intravenous administration at a dose of 50 mg/kg is comparable to exposure in adults after an intravenous dose of 2 g. The absolute bioavailability of cefepime in eight patients after intramuscular injection at a dose of 50 mg/kg was 82.3 (±15)%.

Indications for use

infectious diseases caused by spawn-sensitive organisms;
lower respiratory tract infections, including pneumonia and bronchitis;
urinary tract infections, both complicated, such as pyelonephritis, and uncomplicated;
infections of the skin and skin structures;
intra-abdominal infections, including peritonitis and biliary tract infections;
gynecological infections;
septicemia;
empirical treatment for febrile neutropenia.

Appropriate tests should be performed to identify the causative microorganism(s) and determine sensitivity to cefepime. However, Zhiosef can be used in the form of monotherapy even before identification of the causative microorganism, since it has a wide spectrum of antibacterial action against gram-positive and gram-negative microorganisms.

Method of administration and dosage

Doses and route of administration vary depending on the sensitivity of the pathogenic microorganisms, the severity of the infection, and the state of the patient’s kidney function.

Adults

Urinary tract infections, mild to moderate:	500 mg – 1 g IV or IM	every 12 hours
Other infections, mild to moderate:	1 g IV or IM	every 12 hours
Severe infections:	2 g i.v.	every 12 hours
Very severe and life-threatening infections:	2 g i.v.	every 8 hours

Children (from 2 months to 16 years)

The maximum dose for children should not exceed the recommended dose for adults. The usual recommended dose for children weighing up to 40 kg for complicated or uncomplicated urinary tract infections (including pyelonephritis), uncomplicated infections of the skin and skin structures, pneumonia, as well as for the empirical treatment of neutropenic fever is 50 mg/kg every 12 hours (patients with neutropenic fever). fever every 8 hours).

The usual duration of treatment is 7-10 days; Severe infections may require longer treatment.

Impaired kidney function

In patients with impaired renal function (creatinine clearance <30 ml/min), the dose of Zhiosef a should be adjusted. The initial dose of Giosef should be the same as for patients with normal renal function. Recommended maintenance doses of Zhiosef are presented in the table.

Creatinine clearance (ml/min)	Initial normal recommended doses
Creatinine clearance (ml/min)	2 g every 8 hours	2 g every 12 hours	1 g every 12 hours
> 30	Normal dose, no adjustment required
11 – 30	1 g every 12 hours	1 g every 24 hours	500 mg every 24 hours
< 10	1 g every 24 hours	500 mg every 24 hours	250 mg every 24 hours

When only steady-state serum creatinine concentration data are available, the following formula can be used to determine creatinine clearance:

Men: Creatinine clearance (ml/min) =

weight (kg) x 140 — age

72 x serum creatinine (mg/dL)

Women: above value x 0.85

In patients on hemodialysis, approximately 68% of the total amount of cefepime is removed from the body within 3 hours. At the end of each dialysis session, a repeat dose equal to the original dose must be administered. In patients undergoing continuous ambulatory peritoneal dialysis, cefepime can be used at the initial normal recommended doses, i.e. 500 mg, 1 g or 2 g depending on the severity of the infection, with the interval between doses being 48 hours.

There are no data on the use of the drug in children with impaired renal function. Since the pharmacokinetics of cefepime in adults and children is similar (see PHARMACOKINETICS), the same dosage modifications are recommended for children with impaired renal function as for adults.

Administration of the drug

Giosef can be administered intravenously or by deep intramuscular injection into a large muscle mass (for example, the upper, outer quadrant of the gluteal muscle).

Intravenous administration

The intravenous route of administration is preferred for patients with severe or life-threatening infections, especially those at risk of shock.

For intravenous administration, Giosef is dissolved in 5 or 10 ml of sterile water for injection, 5% glucose solution for injection or 0.9% sodium chloride solution, as indicated in the table below, and administered intravenously over 3-5 minutes. For administration through an intravenous infusion system, the prepared solution is combined with other intravenous infusion solutions and administered over at least 30 minutes. Solutions of the drug Zhiosef in concentrations from 1 to 40 mg/ml are compatible with the following parenteral solutions: 0.9% sodium chloride solution for injection; 5% or 10% glucose solutions for injection;

To avoid possible drug interactions with other drugs, solutions of Zhiosef (as well as most other beta-lactam antibiotics) should not be administered simultaneously with solutions of metronidazole, vancomycin, gentamicin, tobramycin sulfate and netilmicin sulfate. When prescribing Zhiosef with the listed drugs, each antibiotic should be administered separately.

Intramuscular administration

Giosef is dissolved in sterile water for injection, 5% glucose solution for injection or 0.9% sodium chloride solution for injection, bacteriostatic water for injection with paraben or benzyl alcohol, 0.5% or 1% solution of lidocaine hydrochloride.

Like other parenteral drugs, prepared solutions of the drug should be checked for the absence of mechanical inclusions before administration.

During storage, the powder in the vial or solution may darken, but this does not affect the activity of the drug.

Precautions/Warnings

It is necessary to accurately determine whether the patient has previously had immediate hypersensitivity reactions to cefepime, cephalosporins, penicillins or other beta-lactam antibiotics. Antibiotics should be used with caution in all patients with any form of allergies, especially to drugs. If an allergic reaction occurs, use of the drug should be discontinued. Severe immediate hypersensitivity reactions may require the use of epinephrine and other forms of supportive treatment.

Cases of pseudomembranous colitis have been reported with the use of almost all broad-spectrum antibiotics. Therefore, it is important to keep this diagnosis in mind if diarrhea occurs during treatment with Giosef. Mild forms of colitis may respond to discontinuation of the drug; moderate or severe cases may require special treatment.

As with other antibiotics, the use of Giosef can lead to the colonization of insensitive microflora. If superinfections develop during treatment, appropriate measures must be taken.

Side effects

Giosef is usually well tolerated. In clinical trials, the incidence of side effects associated with the use of Giosef was low. The most common side effects were gastrointestinal symptoms and hypersensitivity reactions. The following are side effects that occurred with a frequency of 0.3-1% (exceptions are given in parentheses):

Hypersensitivity: rash (2.8%), itching (1.3%), fever
Gastrointestinal tract: diarrhea (3.6%), nausea (3%), vomiting (2.3%), constipation (1.4%), abdominal pain (1.2%), dyspepsia< /li>
Cardiovascular system: chest pain, tachycardia
Respiratory system: cough, sore throat, shortness of breath
Central nervous system: headaches (3.4%), dizziness, insomnia, paresthesia, anxiety, confusion
Other: asthenia, sweating, vaginitis, peripheral edema, back pain

Anaphylactic reactions and convulsions were observed with a frequency of <0.1%.

Local reactions at the point of intravenous infusion (phlebitis and inflammation) were observed in 3.3% of patients. When administered intramuscularly, Zhiosef was very well tolerated, and inflammation or pain at the injection point was observed in only 1.5% of patients.

Deviations of laboratory test data: During clinical In the trials below, side effects were transient and occurred at a rate of £2% (exceptions in parentheses):

elevated alanine aminotransferase (3.2%), aspartate aminotransferase (2.7%), alkaline phosphatase, total bilirubin, anemia, eosinophilia, increased prothrombin time or PTT, and a positive Coombs test without hemolysis (18.3%). A temporary increase in blood urea nitrogen and/or serum creatinine and transient thrombocytopenia were observed in <0.5% of patients. Transient leukopenia and neutropenia (<0.5%) were also observed.

The following side effects and altered laboratory findings have also been reported for other cephalosporin class antibiotics: urticaria, Stevens-Johnson syndrome, erythema multiplex, toxic epidermal necrolysis, colitis, renal dysfunction, toxic nephropathy, aplastic anemia, hemolytic anemia, bleeding, seizures, liver dysfunction, including cholestasis, and false-positive results of urine glucose tests.

Contraindications

Zhiosef is contraindicated in patients with immediate hypersensitivity reactions to cefepime or tazobactam, as well as to cephalosporin class antibiotics, penicillins or other beta-lactam antibiotics.

Drug interactions

With the simultaneous administration of Cefepime solution with solutions of metronidazole, vancomycin, gentamicin, tobramycin sulfate and netilmicin sulfate, pharmaceutical interaction is possible. If it is necessary to prescribe them simultaneously, each antibiotic should be administered separately.

Cefepime is pharmaceutically incompatible with heparin.

Diuretics, aminoglycosides, polymyxin B reduce the tubular secretion of cefepime and increase its concentration in the blood serum, lengthen T_1/2, and increase nephrotoxicity (increases the risk of developing nephronecrosis).

Non-steroidal anti-inflammatory drugs, by slowing down the elimination of cephalosporins, increase the risk of bleeding.

Special instructions

Use during pregnancy and lactation

Animal testing has demonstrated no effects on reproduction and no harmful effects on the fetus, but adequate and well-controlled studies have not been conducted in pregnant women. The drug should be used during pregnancy only under medical supervision.

Giosef is excreted into human breast milk in very low concentrations. However, during lactation the drug should be used with caution.

Use in children

The safety and effectiveness of Giosef in the treatment of uncomplicated and complicated urinary tract infections (including pyelonephritis), uncomplicated infections of the skin and skin structures, pneumonia, and in the empirical treatment of neutropenic fever have been established in age groups from 2 months to 16 years. The appropriateness of the use of Giosef in these age groups is supported by the results of adequate and well-controlled trials of cefepime in adults and additional pharmacokinetic and safety data obtained from pediatric trials (see PHARMACOKINETICS).

Safety and effectiveness in children less than 2 months of age have not been established. There are no sufficient clinical data to support the use of Giosef a in children under 2 months of age or in the treatment of children with severe infections suspected of being caused byHaemophilus influenzaetype b.

Influence on the ability to drive a car and operate complex machinery

Considering the side effects of the drug (headache, dizziness), caution should be exercised when driving a car and operating other potentially dangerous mechanisms. The question of the possibility of engaging in potentially hazardous activities is decided by the attending physician only after assessing the patient’s individual response to the drug.

The drug should not be used after the expiration date and should be stored out of the reach of children.

Overdose

In cases of significant excess of recommended doses, especially in patients with impaired renal function, the use of dialysis will speed up the removal of Gioseph a from the body; in this case, hemodialysis is preferable to peritoneal dialysis.

Issue form

1.125 g, 1.250 g and 1.5 g of the drug in vials, hermetically sealed with rubber stoppers, crimped caps, included in a set with a solvent — water for injection in a 10.0 ml ampoule and instructions for use in cardboard boxes.

Storage conditions

Store at a temperature not exceeding 30^oС, in a place protected from light.

Prepared solutions of the drug for intramuscular and intravenous injections are stable for 24 hours at room temperature or 7 days when stored in the refrigerator (2-8^oC).

Expiration date

2 years.

Conditions for dispensing from pharmacies

On prescription.

Manufacturer

“Zeiss Pharmaceuticals Pvt. Ltd.” India

Name and address of the organization accepting claims (suggestions) regarding the quality of medicines in the territory of the Republic of Uzbekistan

100057, Republic of Uzbekistan, Tashkent, st. Usta Shirin, 117

Tel: 99(871) 2281692 (93/94)

Fax: 99(871) 2281695

www.shayanafarm.< u>uz, shayanafarm< u>@yahoo.com

GIOCEF

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GIOCEF

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