Fortacef

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FORTACEF FORTACEF®

Composition:

Active substance: cefepime;

1 vial contains cefepime hydrochloride equivalent to 1000 mg of cefepime;

Excipient: L-arginine.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: powder from white to yellowish in color.

Pharmacotherapeutic group.

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

ATC code J01D E01.

Pharmacological Properties

Pharmacodynamics.

Cefepime is a broad-spectrum β-lactam cephalosporin antibiotic of the fourth generation intended for parenteral administration. It exerts a bactericidal effect. It is active against both 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 chromosomally encoded β-lactamases, and rapidly penetrates Gram-negative bacterial cells.

Cefepime is active against the following:

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 intermediate resistance to penicillin — MIC [minimum inhibitory concentration] from 0.1 to 0.3 mcg/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. oxytoca, K. ozaenae; Enterobacter spp., including E. cloacae, E. aerogenes, E. agglomerans, E. sakazakii; Proteus spp., including P. mirabilis, P. vulgaris; Acinetobacter calcoaceticus (including subspecies Anitratus, Iwoffi); 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 (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 cavity microorganisms belonging to Bacteroides; Clostridium perfringens; Fusobacterium spp.; Mobiluncus spp.; Peptostreptococcus spp.; Veillonella spp.

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

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

Pharmacokinetics.

Maximum plasma concentration of the drug is achieved within 0.5 hours after intravenous administration and within 2 hours after intramuscular administration (1 g dose).

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

Table 1

Protein binding of cefepime to plasma proteins is less than 19% and does not depend on the drug concentration in blood serum. It poorly penetrates through the intact blood-brain barrier. However, during meningitis, it reaches therapeutic concentrations in cerebrospinal fluid. Significant concentrations of cefepime are found in urine, bile, peritoneal fluid, bronchial secretions, gallbladder tissue, appendix, and prostate tissue. The volume of distribution is 0.25 L/kg; in children aged 2 months to 16 years, it is 0.33 L/kg. Cefepime is metabolized to N-methylpyrrolidine, which rapidly converts into N-methylpyrrolidine oxide. Cefepime is primarily eliminated via glomerular filtration (total clearance of cefepime is approximately 120 mL/min, with mean renal clearance being 110 mL/min). Approximately 85% of the administered dose is excreted unchanged in urine, 1% as N-methylpyrrolidine, approximately 6.8% as N-methylpyrrolidine oxide, and approximately 2.5% as the cefepime epimer. The mean elimination half-life is approximately 2 hours. In volunteers receiving doses up to 2 g intravenously every 8 hours for 9 days, no drug accumulation was observed.

Dose adjustment of cefepime is not required for patients aged 65 years and older with normal renal function, despite their lower renal clearance compared to younger patients. In patients with impaired renal function, the elimination half-life increases. On average, the half-life of cefepime during hemodialysis is 13 hours and during peritoneal dialysis is 19 hours. The pharmacokinetics of cefepime in patients with hepatic impairment are not altered. Dose adjustment is not necessary for these patients.

Clinical characteristics.

Indications.

Adults.

Infections caused by microorganisms sensitive to cefepime:

• respiratory tract infections, including pneumonia;
• uncomplicated skin and subcutaneous tissue infections;
• complicated intra-abdominal infections (used in combination with metronidazole);
• uncomplicated and complicated urinary tract infections (including pyelonephritis);
• septicemia.

For empirical therapy in patients with febrile neutropenia.

For prophylaxis of postoperative complications in intra-abdominal surgery.

Children.

Pneumonia.

Urinary tract infections, including pyelonephritis.

Skin and subcutaneous tissue infections.

For empirical therapy in patients with febrile neutropenia.

Bacterial meningitis.

Contraindications.

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 at concentrations from 1 to 40 mg/mL is compatible with the following parenteral solutions: 0.9% sodium chloride injection; 5% and 10% dextrose injection; 6 M sodium lactate injection; 5% dextrose and 0.9% sodium chloride injection; Ringer’s lactate with 5% dextrose injection.

To avoid potential drug interactions, cefepime should not be administered simultaneously with metronidazole, vancomycin, gentamicin, tobramycin sulfate, or netilmicin sulfate solutions. When co-administered with these agents, each antibiotic should be administered separately.

Diuretics (such as furosemide) and aminoglycosides reduce tubular secretion of cefepime, increase its serum concentration, prolong its elimination half-life, enhance nephrotoxicity, and increase the risk of nephrotoxicity and renal tubular necrosis. Concomitant use of cefepime and aminoglycosides increases the risk of ototoxic effects of the latter.

Effect on laboratory test results.

Cefepime may cause false-positive glucose in urine tests when using Benedict’s reagent. Enzymatic glucose tests based on glucose oxidase reaction are recommended.

Special precautions for use.

It is necessary to carefully determine whether the patient has previously experienced 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 drug allergies. If an allergic reaction occurs, administration of the drug must be discontinued. Severe hypersensitivity reactions may require the use of epinephrine, hydrocortisone, antihistamines, and other emergency measures.

During prolonged treatment, liver and kidney function tests and hematopoietic system parameters should be monitored regularly.

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

Appropriate tests should be performed to identify the causative microorganism(s) and determine susceptibility to cefepime. Cefepime may be used as monotherapy prior to identification of the causative microorganism(s), due to its broad-spectrum antibacterial activity against both gram-positive and gram-negative microorganisms. In patients at risk of mixed aerobic-anaerobic infection (including Bacteroides fragilis), treatment with cefepime may be initiated in combination with an agent active against anaerobes, pending identification of the pathogen.

Dose adjustment of cefepime is not required for patients aged 65 years and older with normal renal function, despite lower renal clearance compared to younger patients. Elderly patients may have reduced renal function; therefore, dose selection should be cautious, and renal function must be monitored.

Use with caution in patients with gastrointestinal disorders, particularly colitis.

Prothrombin time should be monitored.

Dosage adjustment of the drug is required in patients with impaired renal function (creatinine clearance < 60 mL/min) to compensate for reduced renal elimination. Since serum antibiotic concentrations may persist longer in patients with renal insufficiency or other conditions that may impair renal function, even at usual doses, the maintenance dose of cefepime should be reduced in such patients. The degree of renal impairment, severity of infection, and susceptibility of the causative organisms should be considered when determining the subsequent dose.

Serious adverse reactions such as reversible encephalopathy (confusion, including altered consciousness), myoclonus, seizures, and/or renal failure have been observed most frequently in patients with renal insufficiency receiving doses exceeding the recommended dose, and in elderly patients with renal insufficiency receiving recommended doses of cefepime. Some cases have occurred in patients receiving doses adjusted according to renal function. Symptoms of nephrotoxicity are usually reversible and resolve after discontinuation of cefepime and/or after hemodialysis.

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

Broad-spectrum antibiotics, especially when used long-term, may cause pseudomembranous colitis, ranging from mild diarrhea to fatal colitis. Therefore, the development of diarrhea during treatment with cefepime should be closely monitored. Mild forms of colitis may resolve spontaneously after completion of therapy; moderate or severe cases may require specific treatment.

Antibacterial agents alter the normal flora of the colon and may promote overgrowth of Clostridium. Studies indicate that the toxin produced by Clostridium difficile is the primary cause of antibiotic-associated colitis. After confirmation of the diagnosis of pseudomembranous colitis, appropriate therapeutic measures should be initiated. Moderate pseudomembranous colitis may resolve after discontinuation of the drug. In cases of moderate to severe pseudomembranous colitis, administration of fluids and electrolytes, protein supplementation, and an antibacterial agent effective against Clostridium difficile should be considered.

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 therapy should be initiated.

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

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

When lidocaine is used as a solvent for cefepime in children and adults, safety information regarding lidocaine should be taken into account.

It has been demonstrated that L-arginine alters glucose metabolism and simultaneously increases serum calcium levels when administered at doses 33 times higher than 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 adverse effects on the fetus. However, adequate and well-controlled studies in pregnant women have not been conducted; therefore, cefepime should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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

Ability to influence reaction speed when driving vehicles or operating machinery.

Not studied. If dizziness or other adverse effects affecting reaction speed occur, patients should refrain from driving vehicles or operating machinery.

Administration and Dosage.

The medicinal product is intended for parenteral administration. The dose of the drug is determined individually by a physician depending on the severity of the disease, patient's age, site of infection, and renal function. The usual dosage for adults and children with body weight over 40 kg is 1 g administered intravenously or intramuscularly every 12 hours. The usual duration of treatment is 7–10 days. Severe infections may require longer treatment. Dosage recommendations for cefepime in adults are presented in Table 2.

Table 2.

Dosage recommendations for cefepime in adults with creatinine clearance > 60 mL/min.

* Including cases associated with concomitant bacteremia.

** Or until resolution of neutropenia. For patients in whom fever resolves but neutropenia persists for more than 7 days, the need for continuation of antibacterial therapy should be re-evaluated.

*** Intramuscular administration is indicated only for uncomplicated or complicated infections caused by E. coli of mild to moderate severity, when this route of administration is considered more appropriate.

For prophylaxis of infection during surgical procedures. Administer 2 g of the drug intravenously over 30 minutes, 60 minutes prior to the start of surgery. After completion of this infusion, an additional 500 mg of metronidazole should be administered 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 cefepime should be administered 12 hours after the first dose, followed by administration of metronidazole.

Renal function impairment. Dosage adjustment is required for patients with impaired renal function (creatinine clearance less than 30 mL/min). Recommended doses of cefepime for adults are shown in Table 3.

Table 3.

Recommended doses of cefepime for adult patients with impaired renal 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 ambulatory peritoneal dialysis.

If only 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) = value calculated by the above formula × 0.85

During hemodialysis, approximately 68% of the dose is eliminated from the body over 3 hours. 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 initial standard recommended doses of 500 mg, 1 g, or 2 g, depending on the severity of infection, with a dosing interval of 48 hours.

Cefepime should be administered to infants aged 1–2 months only when strictly indicated. Pediatric patients weighing less than 40 kg receiving cefepime therapy should be closely monitored.

Dose reduction or increased dosing intervals are recommended in pediatric patients with impaired renal function.

Calculation of creatinine clearance in pediatric patients:

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)

Infants aged 1 to 2 months. Cefepime should be administered only when strictly indicated 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 in pediatric patients should not exceed the recommended adult dose. The usual recommended dose in 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 in patients with febrile neutropenia or bacterial meningitis). The usual duration of treatment is 7–10 days; severe infections may require longer treatment.

Cefepime should be administered to children weighing 40 kg or more as in adults.

Administration of the drug. Cefepime may be administered intravenously or by deep intramuscular injection into a large muscle (e.g., the upper outer quadrant of the 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 solution, as specified in Table 4. It should be administered intravenously slowly over 3–5 minutes or via an intravenous infusion system.

Intramuscular administration. Cefepime may be dissolved in 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 specified in Table 4.

Table 4

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

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

Children.

To be used in children aged 1 month and older. When lidocaine is used as a solvent, safety information regarding lidocaine should be taken into account. When prescribing the medicinal product to children aged 1 month and older, the physician must carefully adjust the dose based on the patient's age, body weight, severity and type of infection, and renal function.

Overdose.

Symptoms: In cases of significant overdose, especially in patients with impaired renal function, adverse effects are intensified. Symptoms of overdose include encephalopathy accompanied by hallucinations, impaired consciousness, stupor, coma, myoclonus, epileptiform seizures, and neuromuscular excitability.

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

Adverse reactions.

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

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

Hepatobiliary disorders: hepatitis, cholestatic jaundice, decreased prothrombin activity.

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

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

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

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

Cardiovascular disorders: tachycardia, vasodilation, chest pain, peripheral edema.

Renal and urinary disorders: renal failure.

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

Laboratory abnormalities: increased alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin levels; prolonged prothrombin time or partial thromboplastin time (PTT); positive Coombs test without hemolysis; transient increases in blood urea nitrogen and/or serum creatinine; false-positive urine glucose test.

In addition to the above-mentioned adverse reactions, adverse effects typical for cephalosporin antibiotics are possible: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhage, hepatic dysfunction, cholestasis, pancytopenia.

Reporting of adverse reactions after marketing authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua/.

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

Storage conditions.

Store in the original packaging, protected from light, in a place inaccessible to children, at a temperature not exceeding 25 °C. Prepared solutions for intramuscular and intravenous administration may be stored for up to 24 hours at room temperature or up to 7 days in a refrigerator (2–8 °C).

Incompatibility.

Do not mix with other medicinal products in the same container. Use only the solvents specified in the sections "Administration and dosage" and "Interaction with other medicinal products and other forms of interaction."

Packaging.

1 or 5 vials with powder in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

LLC "ISTFARM", Ukraine (packaging of the in bulk form by Hebei Huamin Pharmaceutical Co., Ltd., China).

Manufacturer's address and location of operations.

13, Remontna Street, Kyiv, 02099, Ukraine