Denipim powder for solution for injection 1000 mg vial No. 1

Instructions for Denipim powder for solution for injection 1000 mg vial No. 1

Composition

active ingredient: cefepime;

1 vial contains cefepime hydrochloride equivalent to cefepime 1000 mg (as a sterile mixture of cefepime hydrochloride and L-arginine);

excipient: L-arginine (as part of a sterile mixture with cefepime hydrochloride).

Dosage form

Powder for solution for injection.

Main physicochemical properties: white to yellowish-white powder.

Pharmacotherapeutic group

Antibacterials for systemic use. Other β-lactam antibiotics. Fourth generation cephalosporins. ATX code J01D E01.

Pharmacological properties

Pharmacodynamics

Cefepime inhibits the synthesis of bacterial cell wall enzymes and has a broad spectrum of activity against a variety of Gram-positive and Gram-negative bacteria. Cefepime is highly resistant to hydrolysis by most β-lactamases, has low affinity for β-lactamases encoded by chromosomal genes, and rapidly penetrates Gram-negative bacterial cells.

Cefepime is active against the following microorganisms:

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

gram-negative aerobes: Pseudomonas spp., including P. aeruginosa, P. putida, P. stutzeri; Escherichia coli, Klebsiella spp., including K. pneumoniae, K. oxytoca, K. ozaenae; Enterobacter spp., including E. cloacae, E. aerogenes, E. sakazakii; Proteus spp., including P. mirabilis, P. vulgaris; Acinetobacter calcoaceticus (subsp. anitratus, lwoffi); Aeromonas hydrophila; Capnocytophaga spp.; Citrobacter spp., including C. diversus, C. freundii; Campylobacter jejuni; Gardnerella vaginalis; Haemophilus ducreyi; H. influenzae (including strains producing β-lactamase); H. parainfluenzae; Hafnia alvei; Legionella spp.; Morganella morganii; Moraxella catarrhalis (Branhamella catarrhalis) (including strains producing β-lactamase); Neisseria gonorrhoeae (including β-lactamase producing strains); N. meningitidis; Pantoea agglomerans (known as Enterobacter agglomerans); Providencia spp. (including P. rettgeri, P. stuartii); Salmonella spp.; Serratia (including S. marcescens, S. liquefaciens); Shigella spp.; Yersinia enterocolitica. Cefepime is inactive against many strains of Xanthomonas maltophilia and Pseudomonas maltophilia;

Anaerobes: Bacteroides spp., including B. melaninogenicus and other oral microorganisms belonging to Bacteroides; Clostridium perfringens; Fusobacterium spp.; Mobiluncus spp.; Peptostreptococcus spp.; Veillonella spp. Cefepime is inactive against Bacteroides fragilis and Clostridium difficile.

Pharmacokinetics

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

Table 1. Mean plasma concentrations of cefepime (μg/mL) following intravenous (IV) and intramuscular (IM) administration

Therapeutic concentrations of cefepime are also achieved in urine, bile, peritoneal fluid, bronchial mucus, sputum, prostate, appendix, and gallbladder.

The average elimination half-life of cefepime is approximately 2 hours. In healthy volunteers who received doses of up to 2 g intravenously at 8-hour intervals for 9 days, no accumulation of the drug was observed.

Cefepime is metabolized to N-methylpyrrolidine, which is rapidly converted to N-methylpyrrolidine oxide. The mean total clearance is 120 ml/min. Cefepime is excreted almost exclusively by renal regulation, mainly by glomerular filtration (mean renal clearance is 110 ml/min). Approximately 85% of the administered dose is excreted in the urine as unchanged cefepime, 1% as N-methylpyrrolidine, approximately 6.8% as N-methylpyrrolidine oxide, and approximately 2.5% as the epimer of cefepime. The binding of cefepime to plasma proteins is less than 19% and is independent of serum concentration.

Patients over 65 years of age with normal renal function do not require dose adjustment, despite lower renal clearance compared to younger patients.

Studies in patients with varying degrees of renal impairment have shown an increase in the elimination half-life. The mean elimination half-life in patients with severe renal impairment requiring dialysis is 13 hours for hemodialysis and 19 hours for peritoneal dialysis.

The pharmacokinetics of cefepime are not altered in patients with hepatic impairment or cystic fibrosis. No dose adjustment is necessary for these patients.

Indication

Adults

Infections caused by microflora sensitive to the drug:

Empirical therapy of patients with neutropenic fever.

Prevention of postoperative complications in intra-abdominal surgery.

Children

Pneumonia; urinary tract infections, including pyelonephritis; skin and subcutaneous tissue infections; septicemia; empirical therapy of patients with neutropenic fever; bacterial meningitis.

Contraindication

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

Interaction with other medicinal products and other types of interactions

When high doses of aminoglycosides are used concomitantly with cefepime, renal function should be closely monitored because of the potential nephrotoxicity and ototoxicity of aminoglycoside antibiotics. Nephrotoxicity has been reported following concomitant use of other cephalosporins with diuretics such as furosemide.

Cefepime at 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 solutions for injection; 6M sodium lactate solution for injection, 5% glucose and 0.9% sodium chloride solution for injection; Ringer's solution with lactate and 5% glucose solution for injection.

To avoid possible drug interactions with other drugs, cefepime solutions (as with most other β-lactam antibiotics) should not be administered simultaneously with solutions of metronidazole, vancomycin, gentamicin, tobramycin sulfate, and netilmicin sulfate. If cefepime is prescribed with these drugs, each antibiotic should be administered separately.

Impact on laboratory test results

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

Application features

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

It is necessary to accurately determine whether the patient has previously had immediate 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. Serious immediate hypersensitivity reactions may require the use of adrenaline and other forms of therapy.

Pseudomembranous colitis has been reported with nearly all broad-spectrum antibiotics. Therefore, it is important to consider the possibility of this condition if diarrhea occurs during treatment with cefepime. Pseudomembranous colitis can range from mild diarrhea to fatal colitis. Mild colitis was reversible and resolved after discontinuation of cefepime; moderate or severe cases may require specific treatment.

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

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

In patients with impaired renal function (creatinine clearance <60 mL/min), the dose of cefepime should be adjusted to compensate for the slow rate of renal elimination. Since prolonged serum concentrations of the antibiotic are possible with conventional doses in patients with renal insufficiency or other conditions that may impair renal function, the maintenance dose should be reduced when cefepime is administered to such patients. The degree of renal impairment, the severity of the infection, and the susceptibility of the organisms causing the infection should be considered when determining the next dose.

With the use of cefepime, as with other drugs of this class, serious adverse reactions such as reversible encephalopathy (confusion, including loss 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 occurred in patients who received doses adjusted taking into account their renal function. In most cases, symptoms of nephrotoxicity were reversible and disappeared after discontinuation of cefepime and/or after hemodialysis.

The use of antibacterial agents causes a change in the normal flora of the colon and may lead to the overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is the main cause of antibiotic-associated colitis. Once the diagnosis of pseudomembranous colitis is confirmed, therapeutic measures should be taken. Pseudomembranous colitis of moderate severity may resolve after discontinuation of the drug. In cases of moderate and severe degrees, the appropriateness of the use of fluids and electrolytes, protein replacement, and the use of an antibacterial agent effective against Clostridium difficile should be considered.

Reservation

The use of cefepime in the absence of a known or suspected bacterial infection or for prophylactic purposes is unlikely to be beneficial, but may increase the risk of the development of bacteria resistant to the drug. Prolonged use of cefepime (as with other antibiotics) may result in the development of superinfection. The patient should be re-evaluated. Appropriate measures should be taken if superinfection occurs.

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 needed.

During the period of use of cefepime, positive results of the direct Coombs test may be obtained. When performing hematological or transfusion procedures, when determining the blood group by cross-matching, when performing an antiglobulin test or during the Coombs test in 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, the safety information for lidocaine should be taken into account.

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

Ability to influence reaction speed when driving vehicles or other mechanisms

Since adverse reactions from the central nervous system may occur during treatment, you should refrain from driving or operating other mechanisms.

Use during pregnancy or breastfeeding

There are no adequate and well-controlled studies in pregnant women, 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 very small amounts, so breastfeeding should be discontinued during treatment with the drug.

Method of administration and doses

The usual adult dosage is 1 g, administered intravenously or intramuscularly at 12-hour intervals. The usual duration of treatment is 7-10 days, but severe infections may require longer treatment.

The dosage and route of administration vary depending on the sensitivity of the causative microorganisms, the severity of the infection, and the functional state of the patient's kidneys.

Dosage recommendations for adults are given in Table 2.

Table 2

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 this, 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 metronidazole is administered.

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

Renal impairment. In patients with renal impairment (creatinine clearance less than 30 ml/min), the dose of the drug should be adjusted.

Table 3. Recommended doses of cefepime for adults

*On the day of dialysis, the injection should be performed after the dialysis session.

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

Men:

body weight (kg) × (140 - age)

creatinine clearance (ml/min) = ---------------------------------------------------;

72 × serum creatinine (mg/dL)

Women:

creatinine clearance (ml/min) = above value × 0.85.

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

For children with impaired renal function, a dose reduction or an increase in the interval between administrations is recommended.

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 aged 1 to 2 months: Cefepime is prescribed only for vital indications at a dose of 30 mg/kg body weight every 12 or 8 hours, depending on the severity of the infection.

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 adults.

Administration of the drug. The drug can be administered intravenously or by deep intramuscular injection into a large muscle mass (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, cefepime should be dissolved in sterile water for injection, 5% glucose solution for injection, or 0.9% sodium chloride solution as indicated in Table 4. Administer intravenously slowly over 3-5 minutes or through an intravenous line.

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

When using lidocaine as a solvent, a skin test should be performed to check for tolerance before administration.

Table 4

As with other parenterally administered drugs, prepared drug solutions must be checked for particulate matter before administration.

Appropriate microbiological studies should be performed to identify the causative organism(s) and determine susceptibility to cefepime. However, cefepime may be used as monotherapy before the causative organism is identified because it has a broad spectrum of antibacterial activity against both Gram-positive and Gram-negative organisms. In patients at risk of mixed aerobic/anaerobic (including Bacteroides fragilis) infections, cefepime may be initiated in combination with an anaerobe-active agent before the causative organism is identified.

Children

Use in children from 1 month of age.

Overdose

Symptoms. In case of significant excess of recommended doses, especially in patients with impaired renal function, the manifestations of adverse reactions 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

Infections and infestations: oral candidiasis, vaginitis, candidiasis.

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

Immune system disorders: hypersensitivity reactions, including anaphylaxis, anaphylactic shock, angioedema.

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

Cardiovascular system: tachycardia, vasodilation.

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

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

From the hepatobiliary system: hepatitis, cholestatic jaundice.

Skin and subcutaneous tissue disorders: rash, itching, urticaria.

Reproductive system: genital itching.

From the urinary system: renal failure.

Others: asthenia, increased sweating, fever, erythema, chest pain, back pain, peripheral edema.

Local reactions at the site of drug administration:

with intravenous administration – phlebitis and inflammation;

with intramuscular injection – pain, inflammation.

Post-marketing studies:

encephalopathy (loss of consciousness, hallucinations, stupor, coma), epileptiform seizures, myoclonus, renal failure; anaphylaxis, including anaphylactic shock, transient leukopenia, neutropenia, agranulocytosis and thrombocytopenia.

Laboratory parameters: increased levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, anemia, eosinophilia, increased prothrombin time or partial thromboplastin time (PTT), and positive Coombs test without hemolysis. Transient increases in blood urea nitrogen and/or serum creatinine and transient thrombocytopenia were observed in less than 0.5% of patients. Transient leukopenia and neutropenia were also observed.

Possible adverse reactions characteristic of cephalosporin antibiotics: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, toxic nephropathy, aplastic anemia, hemolytic anemia, bleeding, liver dysfunction, cholestasis, pancytopenia

Expiration date

2 years.

Do not use after the expiry date stated on the packaging.

Storage conditions

Keep out of reach of children.

Store in the original packaging at a temperature not exceeding 25 °C.

After preparation, the solution should be used immediately after dilution or stored for no more than 24 hours at a temperature of up to 25 °C and 7 days at a temperature of 2 to 8 °C.

The color change does not affect the activity of the drug provided that the drug is stored properly as recommended by the manufacturer.

Packaging

1000 mg of powder for solution for injection in a vial, in a cardboard box.

Vacation category

According to the recipe.

Producer

Swiss Parenterals Ltd.

Location of the manufacturer and its business address

Block II, Plot 402, 412-414 Kerala Industrial Area, GIDC, Near Bavla, Ahmedabad, Gujarat, 382220, India.