Denipim

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DENIPIME (DENIPIME)

Composition:

Active substance: 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 the sterile mixture with cefepime hydrochloride).

Pharmaceutical form. Powder for solution for injection.

Main physicochemical characteristics: powder from white to yellowish-white in color.

Pharmacotherapeutic group.

Antibacterial agents for systemic use. Other β-lactam antibiotics. Fourth-generation cephalosporins. ATC code J01DE01.

Pharmacological Properties

Pharmacodynamics

Cefepime inhibits the synthesis of bacterial cell wall enzymes and has a broad spectrum of activity against various Gram-positive and Gram-negative bacteria. Cefepime is highly resistant to hydrolysis by most β-lactamases, has low affinity for chromosomally mediated β-lactamases, 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 staphylococcal strains, including S. hominis, S. saprophyticus; Streptococcus pyogenes (Group A streptococci); Streptococcus agalactiae (Group B streptococci); Streptococcus pneumoniae (including strains with intermediate penicillin resistance — MIC from 0.1 to 1 mcg/mL); other β-hemolytic streptococci (Groups C, G, F); S. bovis (Group D); Viridans group streptococci. Most enterococcal strains, e.g., 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 β-lactamase-producing strains); H. parainfluenzae; Hafnia alvei; Legionella spp.; Morganella morganii; Moraxella catarrhalis (Branhamella catarrhalis) (including β-lactamase-producing strains); Neisseria gonorrhoeae (including β-lactamase-producing strains); N. meningitidis; Pantoea agglomerans (formerly 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 cavity microorganisms belonging to Bacteroides; Clostridium perfringens; Fusobacterium spp.; Mobiluncus spp.; Peptostreptococcus spp.; Veillonella spp. Cefepime is inactive against Bacteroides fragilis and Clostridium difficile.

Pharmacokinetics

Mean plasma concentrations of cefepime in healthy adult males at various time points after single intravenous and intramuscular administration are shown in Table 1.

Table 1

Mean plasma concentrations of cefepime (mcg/mL) after intravenous (IV)
and intramuscular (IM) administration

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

The average elimination half-life of cefepime is approximately 2 hours. In healthy volunteers receiving doses up to 2 g intravenously every 8 hours for 9 days, no drug accumulation was observed.

Cefepime is metabolized to N-methylpyrrolidine, which is rapidly converted to N-methylpyrrolidine N-oxide. The mean total clearance is 120 mL/min. Cefepime is eliminated almost exclusively via renal mechanisms, primarily by glomerular filtration (mean renal clearance – 110 mL/min). Approximately 85% of the administered dose is excreted in urine as unchanged cefepime, 1% as N-methylpyrrolidine, approximately 6.8% as N-methylpyrrolidine N-oxide, and approximately 2.5% as the cefepime epimer. Plasma protein binding of cefepime is less than 19% and is independent of drug concentration in serum.

Dose adjustment is not required in patients aged 65 years and older with normal renal function, despite their lower renal clearance compared to younger patients.

Studies conducted in patients with various degrees of renal impairment have demonstrated an increased elimination half-life. On average, the half-life in patients with severe renal dysfunction requiring dialysis is 13 hours with hemodialysis and 19 hours with peritoneal dialysis.

The pharmacokinetics of cefepime in patients with hepatic dysfunction or cystic fibrosis is not altered. Dose adjustment is not required for these patients.

Clinical characteristics.

Indications.

Adults

Infections caused by microorganisms sensitive to the drug:

• respiratory tract infections, including pneumonia, bronchitis;
• skin and soft tissue infections;
• intra-abdominal infections, including peritonitis and biliary tract infections;
• urinary tract infections, including pyelonephritis;
• gynecological infections;
• sepsis.

Empirical therapy in patients with febrile neutropenia.

Prophylaxis of postoperative complications in intra-abdominal surgery.

Children

• Pneumonia;
• urinary tract infections, including pyelonephritis;
• skin and soft tissue infections;
• sepsis;
• empirical therapy in patients with febrile neutropenia;
• bacterial meningitis.

Contraindications.

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

Precautionary measures.

Entry of the medicinal product into the external environment should be minimized. Avoid contamination of sewage systems or household waste with the medicinal product.

Interaction with other medicinal products and other types of interactions.

When administering high doses of aminoglycosides concomitantly with cefepime, renal function should be closely monitored due to the potential nephrotoxicity and ototoxicity of aminoglycoside antibiotics. Nephrotoxicity has been reported after concomitant administration 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 injection; 5% and 10% glucose injection; 6M sodium lactate injection; 5% glucose and 0.9% sodium chloride injection; Ringer's lactate solution with 5% glucose injection.

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

Effect on laboratory test results

Cefepime administration may result in false-positive glucose in urine tests when using Benedict's reagent. It is recommended to use glucose tests based on enzymatic glucose oxidation reactions.

Special precautions.

For patients at high risk of severe infections (e.g., those with a history of bone marrow transplantation and impaired bone marrow function due to severe malignant hemolytic disease with severe progressive neutropenia), monotherapy may be insufficient, and combination antimicrobial therapy is indicated.

It is essential to determine precisely whether the patient has previously experienced immediate-type hypersensitivity reactions to cefepime, cephalosporins, penicillins, or other β-lactam antibiotics. Antibiotics should be administered with caution to all patients with any form of allergy, especially drug allergies. If an allergic reaction occurs, administration of the drug should be discontinued. Severe immediate-type hypersensitivity reactions may require treatment with adrenaline and other therapeutic measures.

Cases of pseudomembranous colitis have been reported during the use of nearly all broad-spectrum antibiotics. Therefore, it is important to consider the possibility of this condition developing if diarrhea occurs during cefepime therapy. Pseudomembranous colitis may range from mild diarrhea to fatal colitis. Mild forms of colitis were reversible and resolved after discontinuation of cefepime; moderate or severe cases may require specific treatment.

Cefepime should be used with caution in patients with gastrointestinal disorders, particularly colitis.

During prolonged treatment, it is necessary to monitor liver and kidney function and hematopoietic parameters regularly.

In patients with impaired renal function (creatinine clearance <60 mL/min), the dose of cefepime should be adjusted to compensate for reduced renal elimination. Since prolonged antibiotic serum concentrations are possible with standard doses in patients with renal impairment or other conditions that may worsen kidney function, the maintenance dose should be reduced when administering cefepime to such patients. The degree of renal impairment, severity of infection, and susceptibility of the causative organisms should be considered when determining the subsequent dose.

When using cefepime, as with other drugs in this class, serious adverse reactions such as reversible encephalopathy (confusion, including clouding of consciousness), myoclonia, seizures, and/or renal failure have been observed most frequently in patients with renal impairment receiving doses exceeding the recommended ones, and in elderly patients with renal impairment receiving recommended doses of cefepime. Some cases occurred in patients receiving doses adjusted according to renal function. In most cases, symptoms of nephrotoxicity were reversible and resolved after discontinuation of cefepime and/or hemodialysis.

The pharmacokinetics of cefepime are not altered in patients with hepatic impairment. Dose adjustment in such patients is not required.

Antibacterial agents alter the normal flora of the large intestine and may promote the overgrowth of Clostridium. Studies indicate that the toxin produced by Clostridium difficile is the primary cause of antibiotic-associated colitis. After confirming the diagnosis of pseudomembranous colitis, appropriate therapeutic measures should be initiated. Mild to moderate pseudomembranous colitis may resolve after discontinuation of the drug. In cases of moderate or severe colitis, consideration should be given to fluid and electrolyte replacement, protein supplementation, and administration of an antibacterial agent effective against Clostridium difficile.

Warnings

It is unlikely that prescribing cefepime in the absence of proven or suspected bacterial infection, or for prophylactic use, will be beneficial, but it may increase the risk of emergence of bacteria resistant to this drug. Prolonged use of cefepime (as with other antibiotics) may lead to superinfection. The patient's condition should be re-evaluated periodically. If superinfection develops, appropriate measures should be taken.

Many cephalosporins, including cefepime, are associated with reduced prothrombin activity. Patients at risk include those with impaired liver or kidney function, malnourished patients, and those receiving prolonged courses of antimicrobial therapy. Prothrombin levels should be monitored in patients at risk, and vitamin K should be administered if necessary.

During cefepime therapy, positive results in the direct Coombs test may occur. When performing hematological or transfusion procedures, including blood group determination by cross-matching, or in the Coombs test for newborns whose mothers received cephalosporin antibiotics before delivery, it should be considered that a positive Coombs test may be due to drug administration.

When using lidocaine as a solvent for pediatric use, safety information regarding lidocaine should be taken into account.

It has been demonstrated that L-arginine alters glucose metabolism and simultaneously increases serum potassium levels when administered at doses 33 times higher than the maximum recommended dose of cefepime. Effects at lower doses are still unknown.

Use during pregnancy or breastfeeding.

Adequate and well-controlled studies in pregnant women have not been conducted; therefore, cefepime should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

Cefepime passes into breast milk in very small amounts; therefore, breastfeeding should be discontinued during treatment with this drug.

Ability to influence reaction rate while driving or operating machinery.

Since adverse reactions affecting the central nervous system may occur during treatment, patients should refrain from driving or operating machinery.

Administration and dosage.

The usual dosage for adults is 1 g, which should be administered intravenously or intramuscularly every 12 hours. The usual duration of treatment is 7–10 days; severe infections may require longer treatment.

Dosage and route of administration vary depending on the sensitivity of the causative microorganisms, the severity of the infection, and the patient's renal function.

Dosage recommendations for the drug in adults are presented in Table 2.

Table 2

Prophylaxis of infections during surgical procedures. Administer 2 g of the drug intravenously over 30 minutes to adults, 60 minutes prior to the start of surgery. After this, additionally administer 500 mg of metronidazole intravenously. Metronidazole solutions should not be administered simultaneously with cefepime. The infusion system should be flushed before administration of metronidazole.

During prolonged surgical procedures (exceeding 12 hours), a repeat dose of the same amount of the drug is recommended 12 hours after the first dose, followed by administration of metronidazole.

Renal function impairment. Dose adjustment of the drug is required for patients with impaired renal function (creatinine clearance less than 30 mL/min).

Table 3

Recommended doses of cefepime for adults

*On the day of dialysis, the injection must be administered after the dialysis session.

If only the serum creatinine concentration is known, creatinine clearance can be calculated 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 lasting 3 hours, approximately 68% of the drug dose is eliminated from the body. After each dialysis session, a supplemental dose equal to the initial dose should be administered. For continuous ambulatory peritoneal dialysis, the drug may be administered at the standard initial recommended doses of 500 mg, 1 g, or 2 g, depending on the severity of infection, with a dosing interval of 48 hours.

For children aged 1–2 months, the drug should be prescribed only for life-threatening indications. The condition of children with body weight under 40 kg receiving cefepime should be closely monitored.

For children with impaired renal function, dose reduction or extended dosing intervals are 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 should be administered only for life-threatening indications at a dose of 30 mg/kg body weight every 12 or 8 hours, depending on the severity of infection.

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

For children with body weight of 40 kg or more, cefepime should be administered as in adults.

Administration of the drug. The drug can be administered intravenously or by deep intramuscular injection into a large muscle mass (e.g., the upper outer quadrant of the gluteal muscle – gluteus maximus).

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

For intravenous administration, cefepime should be dissolved in sterile water for injection, 5% dextrose injection solution, or 0.9% sodium chloride injection solution, as specified in Table 4. It should be administered intravenously slowly over 3–5 minutes or via an intravenous infusion system.

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

When lidocaine is used as a diluent, a skin sensitivity test should be performed prior to administration.

Table 4

As with other parenterally administered medicinal products, the prepared solutions of the drug should be inspected for the presence of particulate matter prior to administration.

Appropriate microbiological investigations should be carried out to identify the causative microorganism(s) and to determine susceptibility to cefepime. However, cefepime may be used as monotherapy prior to identification of the causative microorganism, because it has a broad spectrum of antibacterial activity against both gram-positive and gram-negative microorganisms. In patients at risk of mixed aerobic/anaerobic (including Bacteroides fragilis) infection, treatment with cefepime in combination with an agent active against anaerobes may be initiated before identification of the causative organism.

Children.

May be used in children aged 1 month and older.

Overdose.

Symptoms. In case of significant overdose, especially in patients with impaired renal function, adverse reactions may intensify. Symptoms of overdose include encephalopathy accompanied by hallucinations, impaired consciousness, stupor, coma; myoclonus; epileptiform seizures; neuromuscular excitability.

Treatment. Administration of the drug should be discontinued and symptomatic therapy initiated. Hemodialysis accelerates elimination of cefepime from the body; peritoneal dialysis is poorly effective. Severe immediate-type allergic reactions require administration of epinephrine and other forms of intensive therapy.

Adverse Reactions

Infections and infestations: Oral candidiasis, vaginitis, candidiasis.

Blood and lymphatic system disorders: Anemia, eosinophilia, transient leukopenia, neutropenia, agranulocytosis, thrombocytopenia.

Immune system disorders: Hypersensitivity reactions, including anaphylaxis, anaphylactic shock, angioneurotic edema.

Respiratory system disorders: Cough, sore throat, dyspnea, respiratory disorders.

Cardiovascular system disorders: Tachycardia, vasodilation.

Gastrointestinal disorders: Nausea, vomiting, dyspepsia, altered taste sensation, diarrhea, colitis (including pseudomembranous colitis), abdominal pain, constipation.

Nervous system disorders: Dizziness, headache, restlessness, insomnia, paresthesia, confusion/loss of consciousness, seizures/epileptiform attacks, myoclonus, encephalopathy, hallucinations, stupor, coma.

Hepatobiliary disorders: Hepatitis, cholestatic jaundice.

Skin and subcutaneous tissue disorders: Rash, pruritus, urticaria.

Reproductive system disorders: Genital pruritus.

Renal and urinary disorders: Renal failure.

General disorders: Asthenia, increased sweating, fever, erythema, chest pain, back pain, peripheral edema.

Local reactions at the site of administration:

Intravenous administration – phlebitis and inflammation;

Intramuscular administration – pain, inflammation.

Post-marketing surveillance:

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

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

Possible adverse reactions typical for cephalosporin antibiotics: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhages, liver function disorders, cholestasis, pancytopenia.

Shelf life. 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 reconstitution, the solution should be used immediately or stored for no more than 24 hours at a temperature up to 25 °C or for up to 7 days at a temperature between 2 and 8 °C.

Color change does not affect the drug's activity provided the product is stored properly as recommended by the manufacturer.

Incompatibilities.

Do not mix with other medicinal products in the same container. Use only the solvents specified in the section "Administration and dosage."

Packaging.

1000 mg of powder for solution for injection in a vial, 1 vial per carton box.

Prescription status. Prescription only.

Manufacturer.

Ananta Medicare Limited.

Manufacturer’s address.

Chak 17 ML, Agro Food Park Road, RIICO Industrial Area, Udaipurwati, Sri Ganganagar-335002 (Rajasthan), India.

Marketing Authorization Holder.

Ananta Medicare Ltd.

Address of the Marketing Authorization Holder and/or its representative.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.