Cefepime Astra powder for solution for injection 1000 mg vial No. 1

Instructions for use Cefepime Astra powder for solution for injection 1000 mg vial No. 1

Composition

active ingredient: cefepime;

1 vial contains cefepime hydrochloride equivalent to cefepime 500 mg or 1000 mg;

excipient: L-arginine.

Dosage form

Powder for solution for injection.

Main physicochemical properties: white to yellowish powder.

Pharmacotherapeutic group

Antibacterials for systemic use. Other β-lactam antibiotics. Fourth-generation cephalosporins. Cefepime.

ATX code J01D E01.

Pharmacological properties

Pharmacodynamics.

Cefepime is a broad-spectrum fourth-generation β-lactam cephalosporin antibiotic for parenteral use. It has a bactericidal effect. It is active against gram-positive and gram-negative bacteria, including most strains resistant to aminoglycosides or third-generation cephalosporin antibiotics. Cefepime inhibits the synthesis of bacterial cell wall enzymes. The drug is highly resistant to hydrolysis by β-lactamases, has low affinity for β-lactamases encoded by chromosomal genes, and rapidly penetrates gram-negative bacterial cells.

Cefepime is active against:

Gram-positive aerobes: Staphylococcus aureus, Staphylococcus epidermidis (including β-lactamase-producing strains), Staphylococcus hominis, Staphylococcus saprophyticus, Streptococcus pyogenes (group A), Streptococcus agalactiae (group B), Streptococcus pneumoniae (including strains with moderate resistance to penicillin - MIC (minimum inhibitory concentration) from 0.1 to 0.3 μg/ml), other β-hemolytic streptococci (groups C, G, F), Streptococcus bovis (group D), Streptococcus viridans;

Gram-negative aerobes: Pseudomonas spp., including P. aeruginosa, P. putida, P. stutzeri; Escherichia coli, Klebsiella spp., including K. pneumoniae, K. okhutosa, K. ozaenae; Enterobacter spp., including E. cloacae, E. aerogenes, E. agglomerans, E. sakazakii; Proteus spp., including P. mirabilis, P. vulgaris; Acinetobacter calcoaceticus (including subfamilies Anitratus, lwoffi); Aeromonas hydrophila; Capnocytophaga spp.; Citrobacter spp., including C. diversus, C. freundii; Campylobacter jejuni; Gardnerella vaginalis; Haemophilus ducreyi; H. influenzae (including β-lactamase-producing strains): H. parainfluenzae; Haemophilus alvei: Legionella spp.; Organella morganii; Moraxella (Branhamella) catarrhalis (including β-lactamase producing strains); Neisseria gonorrhoeae (including β-lactamase producing strains); N. meningitidis; Providencia spp. (including P. rettgeri, P. stuartii); Salmonella spp.; Serratia (including S. marcescens, S. liquefaciens); Shigella spp.; Yersinia enterocolitica;

anaerobes: Bacteroides spp., including B. melaninogenicus and other oral microorganisms belonging to Bacteroides; Clostridium perfringens; Fusobacterium spp.; Mobiluncus spp.; Reptostreptococcus spp.; Veillonella spp.

Most strains of enterococci and methicillin-resistant staphylococci are resistant to most cephalosporin antibiotics, including cefepime.

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

Pharmacokinetics.

The maximum concentration of the drug in blood plasma is reached after 0.5 hours after intravenous administration, and after 2 hours after intramuscular administration (dose 1 g).

The mean therapeutic plasma concentrations of cefepime in healthy adult males at various times after single intravenous (IV) and intramuscular (IM) administration are shown in Table 1.

Table 1

No dose adjustment of cefepime is required for patients over 65 years of age with normal renal function, despite the lower renal clearance compared to younger patients. The elimination half-life is increased in patients with impaired renal function. The average elimination half-life of cefepime during hemodialysis is 13 hours and during peritoneal dialysis is 19 hours. The pharmacokinetics of cefepime are not altered in patients with impaired hepatic function. No dose adjustment is required for these patients.

Indication

Adults.

Infections caused by microflora sensitive to cefepime:

respiratory tract infections, including pneumonia;

uncomplicated infections of the skin and subcutaneous tissue;

complicated intra-abdominal infections (used in combination with metronidazole);

uncomplicated and complicated urinary tract infections (including pyelonephritis);

septicemia.

For empirical therapy of patients with neutropenic fever.

For the prevention of postoperative complications in intra-abdominal surgery.

Children.

Pneumonia;

urinary tract infections, including pyelonephritis;

infections of the skin and subcutaneous tissue;

bacterial meningitis.

For empirical therapy of patients with neutropenic fever.

Contraindication

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

Interaction with other medicinal products and other types of interactions

Cefepime in concentrations from 1 to 40 mg/ml is compatible with the following parenteral solutions: 0.9% sodium chloride solution for injection; 5 and 10% glucose solution for injection; 6 M sodium lactate solution for injection: 5% glucose solution and 0.9% sodium chloride solution for injection; lactated Ringer's solution and 5% glucose solution for injection.

To avoid possible drug interactions, the drug should not be administered simultaneously with solutions of metronidazole, vancomycin, gentamicin, tobramycin sulfate and netilmicin sulfate. In case of concomitant use with these drugs, each antibiotic should be administered separately.

Diuretics (such as furosemide) and aminoglycosides reduce the tubular secretion of cefepime and increase its serum concentration, prolong the half-life, increase nephrotoxicity and increase the risk of nephronecrosis. The simultaneous use of cefepime and aminoglycosides increases the risk of ototoxicity of the latter.

Impact on laboratory test results.

Cefepime may cause a false-positive reaction for glucose in urine when using Benedict's reagent. It is recommended to use glucose tests based on the enzymatic reaction of glucose oxidation.

Application features

It is necessary to accurately determine whether the patient has previously had immediate-type hypersensitivity reactions to cefepime, cephalosporins, penicillins or other β-lactam antibiotics. Antibiotics should be prescribed with caution to all patients with any form of allergy, especially to drugs. If an allergic reaction occurs, the drug should be discontinued. Severe hypersensitivity reactions may require the use of adrenaline, hydrocortisone, antihistamines and other emergency care.

During long-term treatment, it is necessary to regularly monitor the functional parameters of the liver, kidneys and hematopoiesis organs.

For patients at high risk of severe infections (for example, patients with a history of bone marrow transplantation with reduced activity, on the background of malignant hemolytic pathology with severe progressive neutropenia), monotherapy may be insufficient, therefore complex antimicrobial therapy is indicated.

Appropriate tests should be performed to identify the causative organism(s) and determine susceptibility to cefepime. Cefepime may be used as monotherapy before the causative organism(s) is identified, as it has a broad spectrum of antibacterial activity against both Gram-positive and Gram-negative organisms. If there is a risk of mixed aerobic-anaerobic (including Bacteroides fragilis) infection, treatment with the drug in combination with a drug that is active against anaerobes may be initiated before the causative organism is identified.

No dose adjustment of cefepime is necessary for patients over 65 years of age with normal renal function, despite the lower renal clearance compared with younger patients. Elderly patients may have decreased renal function, so caution should be exercised in determining the dose and renal function should be monitored.

Use with caution in patients with digestive tract diseases, especially colitis.

It is necessary to monitor prothrombin time.

With the use of cefepime, as with other drugs of this class, serious adverse reactions such as reversible encephalopathies (confusion, including clouding of consciousness), myoclonus, convulsions and/or renal failure have been observed most often in patients with renal insufficiency who received doses of the drug exceeding the recommended ones and in elderly patients with renal insufficiency on the background of the recommended doses of cefepime. Some cases have been noted in patients who received doses adjusted for renal function. In most cases, symptoms of nephrotoxicity were reversible and disappeared after discontinuation of cefepime and/or after hemodialysis.

The pharmacokinetics of cefepime are not altered in patients with hepatic impairment. No dose adjustment is required for these patients.

Broad-spectrum antibiotics, especially with prolonged use, can cause pseudomembranous colitis with a severity ranging from mild diarrhea to colitis with a fatal outcome, so attention should be paid to the occurrence of diarrhea during treatment with cefepime. Mild forms of colitis may resolve spontaneously after cessation of therapy, moderate or severe conditions may require special treatment.

Antibacterial agents alter the normal flora of the colon and may promote the overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is the primary cause of antibiotic-associated colitis. Once the diagnosis of pseudomembranous colitis is confirmed, therapeutic measures should be taken. Moderate pseudomembranous colitis may be reversible after discontinuation of the drug. In moderate to severe cases, consideration should be given to the need for fluid and electrolyte replacement, protein replacement, and the use of an antibacterial agent effective against Clostridium difficile.

It is unlikely that the use of cefepime in the absence of a proven or suspected bacterial infection or for prophylactic purposes will be beneficial, but it increases the risk of the emergence of bacteria resistant to this drug. Prolonged use of cefepime (as with other antibiotics) may lead to the development of superinfection. The patient should be re-evaluated. If superinfection develops, appropriate treatment should be initiated.

Many cephalosporins, including cefepime, are associated with decreased prothrombin activity. Patients at risk include those with impaired hepatic or renal function, those who are malnourished, and those receiving prolonged antimicrobial therapy. Prothrombin should be monitored in patients at risk and vitamin K should be administered as necessary.

During the period of use of cefepime, positive results of the direct Coombs test may be obtained. When performing hematological or transfusion procedures for cross-matching blood groups, when an antiglobulin test is performed, or during the Coombs test of newborns whose mothers received cephalosporin antibiotics before delivery, it should be taken into account that a positive Coombs test may be the result of the use of the drug.

When using lidocaine as a solvent in children and adults, the safety information for lidocaine should be considered.

L-arginine has been shown to alter glucose metabolism and simultaneously increase serum calcium levels at doses 33 times the maximum recommended dose of cefepime. Effects at lower doses are currently unknown.

Use during pregnancy or breastfeeding

Animal studies have shown no effect on reproductive function and no harmful effects on the fetus. However, adequate and well-controlled studies in pregnant women have not been conducted, therefore cefepime should be prescribed during pregnancy only if the expected benefit to the woman outweighs the potential risk to the fetus.

Cefepime passes into breast milk in small amounts, so breastfeeding should be discontinued during treatment with the drug.

Ability to influence reaction speed when driving vehicles or other mechanisms

Not studied. If dizziness or other side effects occur that may affect the speed of reactions, you should refrain from driving or operating other mechanisms.

Method of administration and doses

The drug is intended for parenteral administration. The dose of the drug is set individually by the doctor, depending on the severity of the disease, the patient's age, the location of the infection, and kidney function. The usual dosage for adults and children weighing more than 40 kg is 1 g intravenously or intramuscularly every 12 hours. The usual duration of treatment is 7–10 days. Severe infections may require longer treatment. Recommendations for the dosage of cefepime for adults are given in Table 2.

Table 2. Cefepime dosage recommendations for adults

with creatinine clearance >60 ml/min.

*Including cases associated with bacteremia.

** Or until resolution of neutropenia. For patients whose fever resolves but who remain neutropenic for more than 7 days, the need for continued antibacterial therapy should be reconsidered.

*** Intramuscular route of administration is only used in mild to moderate uncomplicated or complicated infections caused by E. coli, when intramuscular route of administration is considered more appropriate.

For the prevention of infections during surgical interventions. 60 minutes before the start of surgery, adults should be administered 2 g of the drug intravenously over 30 minutes. After the end of the administration, an additional 500 mg of metronidazole is administered intravenously. Metronidazole solutions should not be administered simultaneously with cefepime. The infusion system should be flushed before the administration of metronidazole.

During prolonged (more than 12 hours) surgical operations, it is recommended to repeat the same dose of cefepime 12 hours after the first dose, followed by metronidazole.

Renal impairment: For patients with renal impairment (creatinine clearance less than 30 ml/min), the dose of the drug should be adjusted. The recommended doses of cefepime for adults are given in Table 3.

Table 3. Recommended doses of cefepime for adult patients

with impaired kidney function

*On hemodialysis days, cefepime should be administered as described in Table 3. If possible, cefepime should be administered at the same time each day.

** Continuous outpatient peritoneal dialysis.

If only the serum creatinine concentration is known, then creatinine clearance can be determined using the following formula:

Men:

body weight (kg) × (140 – age)

creatinine clearance (ml/min) = ______________________________________________

72 × serum creatinine (mg/dL)

Women:

Creatinine clearance (ml/min) = value calculated using the above formula × 0.85.

During hemodialysis, approximately 68% of the dose is removed from the body within 3 hours. After each dialysis session, a second dose equal to the initial dose should be administered. During continuous ambulatory peritoneal dialysis, the drug can be used in the initial normal recommended doses of 500 mg, 1 or 2 g, depending on the severity of the infection, with an interval between administrations of 48 hours.

Children aged 1–2 months should be given the drug only if absolutely necessary. Children weighing up to 40 kg receiving cefepime treatment should be monitored closely.

Children with impaired renal function are recommended to reduce the dose or increase the interval between administrations.

Calculation of creatinine clearance in children:

0.55 × height (cm)

creatinine clearance (ml/min/1.73 m2) = _________________________________________

serum creatinine (mg/dL)

or

0.52 × height (cm)

creatinine clearance (ml/min/1.73 m2) = _________________________________________ – 3.6

serum creatinine (mg/dL)

Children from 2 months of age. The maximum dose for children should not exceed the recommended adult dose. The usual recommended dose for children weighing up to 40 kg for complicated or uncomplicated urinary tract infections (including pyelonephritis), uncomplicated skin infections, pneumonia, and for empirical treatment of febrile neutropenia is 50 mg/kg every 12 hours (every 8 hours for patients with febrile neutropenia and bacterial meningitis). The usual duration of treatment is 7-10 days; severe infections may require longer treatment.

Children weighing 40 kg or more should be prescribed cefepime as for adults.

Administration of the drug. Cefepime can be administered intravenously or by deep intramuscular injection into a large muscle (for example, into the upper outer quadrant of the gluteus maximus).

Intravenous administration. The intravenous route of administration is preferred for patients with severe or life-threatening infections.

For intravenous administration, dissolve the drug in sterile water for injection, 5% glucose solution for injection, or 0.9% sodium chloride solution as indicated in Table 4 below. Administer intravenously slowly over 3–5 minutes or through an intravenous line.

Intramuscular administration. Cefepime can be dissolved in sterile water for injection, 0.9% sodium chloride for injection, 5% glucose for injection, bacteriostatic water for injection with paraben or benzyl alcohol, 0.5% or 1% lidocaine hydrochloride solution at the concentrations listed in Table 4.

Table 4

The prepared cefepime solution should be visually inspected for particulate matter prior to administration.

Prepared solutions of the drug for intramuscular and intravenous administration can be stored for 24 hours at room temperature or 7 days in a refrigerator (2–8 °C).

Children.

Use in children over 1 month of age. When using lidocaine as a solvent, the safety information for lidocaine should be considered. When prescribing the drug to children over 1 month of age, the physician should carefully assess the dose of the drug depending on the age, body weight of the patient, the severity and type of infection, and the state of renal function.

Overdose

Symptoms: in case of significant excess of the recommended doses, especially in patients with impaired renal function, the manifestations of side effects are aggravated. Symptoms of overdose include encephalopathy, accompanied by hallucinations, impaired consciousness, stupor, coma, myoclonus, epileptiform seizures, neuromuscular excitability.

Treatment. The drug should be discontinued and symptomatic therapy should be administered. Hemodialysis accelerates the removal of cefepime from the body; peritoneal dialysis is ineffective. Severe immediate-type allergic reactions require the use of adrenaline and other forms of intensive care.

Adverse reactions

Immune system disorders: hypersensitivity reactions, including anaphylaxis, anaphylactic shock, angioedema, rash, erythema, pruritus, urticaria, fever.

On the part of the digestive tract: nausea, vomiting, oral candidiasis, diarrhea, colitis (including pseudomembranous), constipation, abdominal pain, dyspepsia, change in taste.

From the hepatobiliary system: hepatitis, cholestatic jaundice, decreased prothrombin activity.

Nervous system: dizziness, headache, anxiety, insomnia, paresthesia, confusion/loss of consciousness, convulsions/epileptiform seizures, myoclonus, encephalopathy, hallucinations, stupor, coma.

General disorders and administration site conditions: fever, sweating, chest/back pain, asthenia, injection site conditions including inflammation, phlebitis, pain.

Infections: candidiasis, vaginitis, genital itching, pseudomembranous colitis, other superinfections.

Respiratory system: respiratory disorders, cough, sore throat, shortness of breath.

Cardiovascular system: tachycardia, vasodilation, pain in the heart area, peripheral edema.

From the urinary system: renal failure.

From the blood and lymphatic system: anemia, eosinophilia, transient leukopenia, neutropenia, agranulocytosis, thrombocytopenia.

In addition to the above-mentioned adverse reactions, adverse reactions characteristic of cephalosporin antibiotics are possible: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, toxic nephropathy, aplastic anemia, hemolytic anemia, bleeding, liver dysfunction, cholestasis, pancytopenia.

Expiration date

3 years (from the date of manufacture of the bulk form).

Storage conditions

Store in the original packaging out of the reach of children at a temperature not exceeding 25 ° C. Prepared solutions of the drug for intramuscular and intravenous administration can be stored for 24 hours at room temperature or 7 days in a refrigerator (2–8 ° C).

Incompatibility.

Do not mix in the same container with other medicines. Use the solvents specified in the sections "Method of administration and dosage", "Interaction with other medicines and other types of interactions".

Packaging

Powder vial. 1 or 10 vials in a cardboard box.

Vacation category

According to the recipe.

Producer

LLC "ASTRAPHARM" (packaging from the form in bulk: NSPS Hebei Huamin Pharmaceutical Company Limited, China).

Location of the manufacturer and its business address.

Ukraine, 08132, Kyiv region, Kyiv-Svyatoshynskyi district, Vyshneve, Kyivska st., 6.