Deltacef

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

Composition:

Active substance: cefepime;

1 vial contains cefepime dihydrochloride monohydrate equivalent to 1 g of cefepime;

Excipient: L-arginine.

Pharmaceutical form. Powder for solution for injection or infusion.

Main physicochemical characteristics: powder from white to pale yellow in color.

Pharmacotherapeutic group. Antibacterial agents for systemic use. Other β-lactam antibiotics. Fourth-generation cephalosporins. Cefepime.

ATC code J01D E01.

Pharmacological properties.

Pharmacodynamics.

Cefepime is a β-lactam fourth-generation cephalosporin antibiotic with a broad spectrum of activity, intended for intravenous and intramuscular administration. Cefepime inhibits the synthesis of bacterial cell wall enzymes. It has a broad spectrum of activity against various Gram-positive and Gram-negative bacteria, including most strains resistant to aminoglycosides or third-generation cephalosporin antibiotics. Cefepime is highly stable against hydrolysis by most β-lactamases and rapidly penetrates Gram-negative bacterial cells. Cefepime has low affinity for chromosomally encoded β-lactamases. Moderate affinity of cefepime to PBPs 1a and 1b also contributes to its bactericidal activity. The MBC (minimum bactericidal concentration)/MIC (minimum inhibitory concentration) ratio of cefepime is less than 2 for more than 80% of isolates of all susceptible Gram-positive and Gram-negative bacteria.

Cefepime is active against:

Gram-positive aerobes: Staphylococcus aureus (methicillin-susceptible strains only), Staphylococcus epidermidis (including β-lactamase-producing strains), Staphylococcus hominis, Staphylococcus saprophyticus, Streptococcus pyogenes (including Group A streptococci), Streptococcus agalactiae (Group B streptococci), Streptococcus pneumoniae (including strains with intermediate penicillin resistance – MIC 0.1–1 mcg/mL), other β-hemolytic streptococci (Groups C, G, F), Streptococcus bovis (Group D), Streptococcus viridans;

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

anaerobes: Bacteroides spp., Clostridium perfringens; Fusobacterium spp.; Mobiluncus spp.; Peptostreptococcus spp.; Prevotella melaninogenica (formerly known as Bacteroides melaninogenicus); Veillonella spp. Cefepime is inactive against Clostridium fragilis and Clostridium difficile.

The prevalence of resistance among individual bacterial strains may vary depending on region and time; therefore, it is recommended to obtain local information on strain susceptibility prior to initiating therapy.

Pharmacokinetics.

Mean plasma concentrations of cefepime in healthy adult males at various time points after a single 30-minute intravenous infusion and intramuscular administration are shown in Table 1.

Table 1

Mean plasma concentrations of cefepime (mcg/mL) in healthy adult males

Cefepime is metabolized to N-methylpyrrolidine, which is rapidly converted to N-methylpyrrolidine oxide. Approximately 85% of the administered dose is excreted in urine as unchanged cefepime, 1% as N-methylpyrrolidine, approximately 6.8% as N-methylpyrrolidine oxide, and approximately 2.5% as the cefepime epimer. Plasma protein binding of cefepime is less than 16.4% and is independent of drug concentration in serum.

Elimination of cefepime occurs primarily via renal excretion, with a mean elimination half-life of 2 hours, total clearance of 120 mL/min, and mean renal clearance of 10 mL/min. Cefepime exhibits linear pharmacokinetics over the range of 250 mg to 2 g. There are no data indicating accumulation of cefepime in healthy volunteers receiving clinically significant doses over 9 days.

In patients with severe renal impairment undergoing dialysis, the elimination half-life is 13 hours for hemodialysis and 19 hours for peritoneal dialysis. The pharmacokinetics of cefepime in patients with hepatic impairment is not altered. Dose adjustment is not required in such patients.

Clinical characteristics.

Indications.

Adults

Infections caused by microorganisms sensitive to the drug:

• lower respiratory tract infections (including pneumonia, bronchitis);
• urinary tract infections (uncomplicated and complicated urinary tract infections, including pyelonephritis);
• skin and soft tissue infections;
• intra-abdominal infections (including peritonitis, biliary tract infections);
• gynecological infections;
• treatment of patients with bacteremia caused by any of the infections listed above, or suspected bacteremia;
• empirical therapy in patients with febrile neutropenia

(cefepime as monotherapy is indicated as empirical treatment for patients with febrile neutropenia; for patients at high risk of severe infections (e.g., patients with recent bone marrow transplantation, patients with hypotension, patients with underlying hematologic malignancy, or patients with severe or prolonged neutropenia), antimicrobial monotherapy may be inappropriate; there are insufficient data confirming the efficacy of cefepime monotherapy in such patients);

• prophylaxis of postoperative complications in intra-abdominal surgery.

Children

The medicinal product Deltacef is indicated for children aged 2 months and older for the treatment of infections caused by microorganisms sensitive to cefepime:

• pneumonia;
• skin and soft tissue infections;
• urinary tract infections (uncomplicated and complicated urinary tract infections, including pyelonephritis);
• treatment of patients with bacteremia caused by any of the infections listed above, or suspected bacteremia

(cefepime as monotherapy is indicated as empirical treatment for patients with febrile neutropenia; for patients at high risk of severe infections (e.g., patients with recent bone marrow transplantation, patients with hypotension, patients with underlying hematologic malignancy, or patients with severe or prolonged neutropenia), antimicrobial monotherapy may be inappropriate; there are insufficient data confirming the efficacy of cefepime monotherapy in such patients);

• bacterial meningitis.

To identify possible causative agents, culture and antibiotic susceptibility testing are recommended. Empirical treatment with Deltacef may be initiated before the results of these tests are available; however, therapy should be adjusted accordingly once results are obtained. Due to its broad bactericidal activity against both gram-positive and gram-negative microorganisms, the medicinal product Deltacef can be used as a single agent even before identification of the infecting organism and its susceptibility to cefepime (see section "Pharmacological properties"). In patients at high risk of combined aerobic-anaerobic infection, especially when the microorganism is not susceptible to cefepime, initial treatment should be started concomitantly with anti-anaerobic agents, even before identification of the causative pathogen. When test results become available, combination therapy with Deltacef and other antibiotics may no longer be necessary.

Contraindications.

Hypersensitivity to cefepime or to L-arginine, as well as to cephalosporins, other β-lactam antibiotics (e.g., penicillins, monobactams, and carbapenems).

Interaction with other medicinal products and other forms of interaction.

No available studies. Concomitant use of bacteriostatic antibiotics may interfere with the action of β-lactam antibiotics.

There is a risk of bleeding with combined therapy using anticoagulants, antiplatelet, and anti-aggregant agents.

Probenecid slows renal elimination of cefepime, thereby enhancing its effect.

Cefepime may cause a disulfiram-like (Antabuse) reaction when combined with alcoholic beverages, manifesting as nausea and vomiting.

Non-enzymatic methods for urine glucose testing may also yield false-positive results.

Special precautions for use.

Hypersensitivity. As with all β-lactam antibacterial agents, severe hypersensitivity reactions, sometimes fatal, have been reported. Before initiating therapy with cefepime, it is essential to determine whether the patient has previously experienced hypersensitivity reactions to cefepime, other β-lactam antibiotics, or other drugs. Cefepime should be administered with caution to patients with a history of asthma or allergic diathesis. Careful monitoring of the patient is required during the first administration. If an allergic reaction occurs, the drug should be discontinued immediately. Severe hypersensitivity reactions may require administration of epinephrine and implementation of other therapeutic measures.

Antibacterial activity of cefepime. Since the spectrum of antibacterial activity of cefepime is relatively limited, this medicinal product is not suitable for the treatment of certain types of infections unless the pathogen has been documented and is known to be susceptible, or there is a very high probability of susceptibility to cefepime (see section "Pharmacological properties").

Renal function impairment. Dose adjustment of cefepime is required in patients with impaired renal function (creatinine clearance ≤ 50 mL/min) or other conditions that may impair renal function, to compensate for reduced renal elimination. Since high and prolonged serum antibiotic concentrations may occur at standard doses in patients with renal impairment or other conditions affecting renal 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 appropriate dosage.

When using cefepime, as with other drugs in this class, serious adverse reactions such as reversible encephalopathy (confusion, including altered consciousness), myoclonus, seizures (including non-convulsive epileptic status), and/or renal failure have most frequently been observed in patients with renal impairment who received doses exceeding the recommended ones. In most cases, symptoms of nephrotoxicity were reversible and resolved after discontinuation of cefepime and/or hemodialysis; however, fatal cases have been reported.

Clostridium difficile-associated diarrhea. Diarrhea has been observed with the use of almost all broad-spectrum antibacterial agents, including cefepime, and may range in severity from mild diarrhea to life-threatening pseudomembranous colitis (CDAD). Pseudomembranous colitis should be considered in all patients presenting with diarrhea following antibiotic use. An accurate medical history is essential, as cases of CDAD have been reported up to two months after antibiotic administration. If CDAD is suspected or confirmed, ongoing use of antibiotics not directed against Clostridium difficile should be discontinued immediately.

Effect on laboratory test results. A positive Coombs' test in the absence of hemolysis has been reported in patients receiving cefepime twice daily. Cephalosporin antibiotics may cause false-positive reactions for glucose in urine when using copper reduction tests (Benedict's solution, Fehling's solution, or Clinistix® tablets), but not with enzymatic tests (glucose oxidase) for glycosuria. Therefore, it is recommended to use glucose tests based on enzymatic glucose oxidase reactions.

Elderly patients. Of over 6400 adults who received cefepime in clinical studies, 35% were aged 65 years and older, and 16% were aged 75 years and older. In clinical trials, safety and efficacy in geriatric patients receiving the standard adult dose were comparable to those in non-geriatric patients, provided these patients had no renal dysfunction. Only a slight prolongation of elimination half-life and reduction in renal clearance were observed compared to younger patients. Dose adjustment is necessary in cases of renal impairment. Since cefepime is primarily excreted by the kidneys, the risk of toxic effects is higher in patients with impaired renal function. Given that elderly patients are more likely to have decreased renal function, careful dose selection and monitoring of renal function are recommended. Serious adverse reactions have been observed in elderly patients with renal impairment who did not receive dose adjustments, including reversible encephalopathy (altered mental status with confusion, hallucinations, stupor, and coma), myoclonus, seizures (including non-convulsive epileptic status), and/or renal failure.

Use during pregnancy or breastfeeding.

The safety of cefepime use in pregnant women has not been established. Studies in mice and rabbits did not show any direct or indirect harmful effects on the fetus. However, data evaluating the impact of cefepime on fertility, fetal development, parturition, and postnatal development are insufficient. The potential risk to humans is unknown. Cefepime should be used during pregnancy only if the anticipated benefit justifies the potential risk.

Cefepime may be prescribed during pregnancy only when the expected benefit to the woman outweighs the potential risk to the fetus.

Cefepime is excreted in human milk in very small amounts. The medicinal product Deltacef may be prescribed only when the expected benefit outweighs the potential risk.

Impairment of fertility was not observed in rats. There are no data on the effect of cefepime on human fertility.

Ability to affect reaction speed when driving or operating machinery.

Not studied. However, adverse reactions such as altered consciousness, dizziness, confusion, or hallucinations may affect the ability to drive or operate machinery.

Administration and Dosage.

The dosage and route of administration depend on the severity of the disease, renal function, and the patient's overall condition. The medicinal product Deltacef can be administered intravenously or by deep intramuscular injection into a large muscle. Solution preparation for cefepime is provided in Table 2.

Table 2

Intravenous administration. The intravenous route is preferred for patients with severe or life-threatening infections, especially when shock is possible. For intravenous administration, cefepime should be dissolved in sterile water for injection, 5 % dextrose injection solution, or 0.9 % sodium chloride solution, as indicated in Table 2. Administer intravenously slowly over 3–5 minutes or via an intravenous infusion system.

For continuous intravenous infusion, reconstitute the Deltacef solution as recommended (the same as for direct intravenous administration) and add the appropriate volume of the reconstituted solution to one of the compatible intravenous fluids in an intravenous infusion system. The resulting solution should be administered over approximately 30 minutes.

Intramuscular administration. Cefepime should be dissolved in one of the following diluents according to the dilution volumes specified in Table 2: sterile water for injection, 0.9 % sodium chloride solution for injection, 5 % dextrose solution for injection, bacteriostatic water for injection with parabens or benzyl alcohol, and administered by deep intramuscular injection into a large muscle (e.g., the upper outer quadrant of the gluteus maximus). In a pharmacokinetic study, doses up to 1 g (volume less than 3.1 mL) were administered at a single injection site. The maximum intramuscular dose (2 g/6.2 mL) should be administered at two injection sites.

Although Deltacef can be reconstituted with 0.5 % or 1.0 % lidocaine hydrochloride, this is generally not necessary, as cefepime causes minimal or no pain upon intramuscular injection.

Dosage recommendations for cefepime in adults with body weight over 40 kg and normal renal function are provided in Table 3.

Table 3

* The usual duration of treatment is 7–10 days; severe infections may require longer treatment. For the treatment of neutropenia, the duration of treatment should last at least 7 days until neutropenia resolves.

For the prevention of infections during surgical procedures (adults). Administer 2 g of the drug intravenously over 30 minutes, 60 minutes before the start of surgery. A single dose of 500 mg metronidazole should be administered intravenously immediately after completion of the cefepime infusion. Preparation and administration of metronidazole are described in the medical instructions for use. Due to incompatibility between metronidazole and cefepime, they must not be mixed in the same container. Before administering metronidazole, the infusion system should be flushed with a compatible fluid. During prolonged surgical procedures (exceeding 12 hours), a repeat dose of the same amount of cefepime is recommended 12 hours after the first dose, followed by subsequent administration of metronidazole.

Renal function impairment. For patients with impaired renal function, the dose of the drug must be adjusted to compensate for reduced renal excretion.

The recommended initial dose of cefepime in patients with mild to moderate renal impairment is the same as in patients with normal renal function. The maintenance dose for adults with renal impairment is shown in Table 4.

Table 4

*Pharmacokinetic modeling demonstrates the need to reduce the dose in such patients.

Dosing recommendations for cefepime in patients undergoing hemodialysis:

First day of therapy – 1 g daily, then 500 mg every 24 hours for all infections except neutropenia, where the daily dose is 1 g. Cefepime should be administered after completion of the hemodialysis procedure. Whenever possible, cefepime should be administered at the same time each day. Serum creatinine should reflect a stable renal function status. If only serum creatinine concentration is known, creatinine clearance can be calculated using the formula below:

Men:

weight (kg) × (140 – age) × 1.23

creatinine clearance (mL/min) = ______________________________________________;

72 × serum creatinine (mg/dL)

Women: creatinine clearance (mL/min) = value in men × 0.85.

Patients on dialysis. During 3-hour hemodialysis, approximately 68% of the dose is eliminated from the body. For continuous ambulatory peritoneal dialysis, the drug may be administered at the initial recommended doses of 500 mg, 1 g, or 2 g depending on the severity of infection, with a dosing interval of 48 hours.

Hepatic impairment. Dose adjustment is not required in patients with hepatic impairment.

Recommended dosing in children with normal renal function (aged 2 months and older).

Pneumonia, urinary tract infections, skin and soft tissue infections: in children aged 2 months and older with body weight less than 40 kg: 50 mg/kg every 12 hours for 10 days; in severe infections – every 8 hours.

Septicemia, bacterial meningitis, and empirical treatment of febrile neutropenia: in children aged 2 months and older with body weight less than 40 kg: 50 mg/kg every 8 hours for 7–10 days.

There are no official data on the use of Deltacef in children under 2 months of age. However, based on modeled clinical pharmacokinetic data showing a dose of 50 mg/kg in children aged 2 months and older, a dose of 30 mg/kg every 12 or 8 hours may be used in children aged 1 to 2 months. Both doses – 50 mg/kg in children aged 2 months and older and 30 mg/kg in children aged 1 to 2 months – are comparable to the adult dose of 2 g. Careful monitoring is recommended.

Children with body weight of 40 kg or more should receive cefepime as in adults. The dose for children should not exceed the maximum adult dose of 2 g every 8 hours. Limited data are available on intramuscular administration in children.

Recommended dosing in children with renal impairment

Since Deltacef is eliminated exclusively by the kidneys, the dose should also be adjusted in patients with impaired renal function. The same prolongation of dosing intervals and/or dose reduction as shown in Table 4 should be applied. If only serum creatinine level is available, creatinine clearance can be calculated using the following formula:

0.55 × height (cm)

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

serum creatinine (mg/100 mL)

or

0.52 × height (cm)

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

serum creatinine (mg/100 mL)

Elderly patients. Since elderly patients are more likely to have impaired renal function, the dose should be carefully selected and renal function monitored. Dose adjustment is recommended if renal function is impaired.

Children. May be used in children aged 1 month and older.

Overdose.

In cases of significant overdose, especially in patients with impaired renal function, hemodialysis accelerates the elimination of cefepime from the body; peritoneal dialysis is poorly effective. Accidental overdoses have occurred when high doses were administered to patients with impaired renal function. Symptoms of overdose include encephalopathy accompanied by hallucinations, altered consciousness, stupor, coma, myoclonus, epileptiform seizures, and neuromuscular excitability.

Adverse Reactions

All reported adverse reactions are listed below by system organ class and frequency, using the following frequency categories: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), and frequency not known (cannot be estimated from available data).

Infections and infestations: uncommon – oral candidiasis, vaginal infections; rare – candidiasis.

Blood and lymphatic system disorders: common – anemia, eosinophilia; uncommon – thrombocytopenia, leukopenia, neutropenia; frequency not known – aplastic anemia, hemolytic anemia, agranulocytosis.

Immune system disorders: rare – anaphylactic reactions, angioedema (Quincke's edema); frequency not known – anaphylactic shock.

Psychiatric disorders: frequency not known – confusion, hallucinations.

Nervous system disorders: uncommon – headache; rare – seizures, paresthesia, dysgeusia, dizziness; frequency not known – coma, stupor, encephalopathy, disturbance of consciousness, myoclonia.

Cardiovascular disorders: common – phlebitis at injection site; rare – vasodilation; frequency not known – hemorrhage.

Respiratory system disorders: rare – dyspnea.

Gastrointestinal disorders: common – diarrhea; uncommon – colitis (including pseudomembranous colitis), nausea, vomiting; rare – abdominal pain, constipation; frequency not known – gastrointestinal disorders.

Skin and subcutaneous tissue disorders: common – rash; uncommon – erythema, pruritus, urticaria; frequency not known – Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis.

Renal and urinary disorders: frequency not known – renal failure, toxic nephropathy.

Reproductive system and breast disorders: rare – genital pruritus.

General disorders and administration site conditions: common – infusion site reactions, injection site pain, injection site inflammation; uncommon – pyrexia, infusion site inflammation; rare – chills.

Investigations (laboratory findings): very common – positive Coombs test; common – increased alkaline phosphatase, increased alanine aminotransferase, increased aspartate aminotransferase, increased blood bilirubin, prolonged prothrombin time, prolonged partial thromboplastin time; uncommon – increased blood urea nitrogen, increased blood creatinine; frequency not known – false positive urine glucose test.

Pediatric population: In neonates, infants, and children, the safety profile of cefepime was similar to that observed in adults. In clinical studies, rash was the most commonly reported adverse reaction and was causally related to cefepime.

Reporting of suspected adverse reactions. Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life. 2 years.

Storage conditions. Store at temperatures not exceeding 30 °C. Keep the vial in the outer carton to protect from light, and store in a place inaccessible to children.

Incompatibilities.

Solutions of cefepime, like most β-lactam antibiotics, must not be mixed in the same syringe or infusion system with the following antibiotics: metronidazole, vancomycin, gentamicin, tobramycin sulfate, due to possible physical or chemical incompatibility. If concomitant therapy is required, these drugs should be administered separately.

Packaging. Vial with powder. 1 or 10 vials per cardboard box.

Prescription status. Prescription only.

Manufacturer. Medocemie Limited / Medochemie Limited.

Manufacturer's address and place of business.
Agios Athanassios Industrial Area, Michail Irakleous 2, Agios Athanassios, Limassol, 4101, Cyprus / Agios Athanassios Industrial Area, Michail Irakleous 2, Agios Athanassios, Limassol, 4101, Cyprus.