Cepim

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

Composition:

Active substance: cefepime;

1 vial contains cefepime hydrochloride equivalent to 1 g of cefepime;

Excipient: L-arginine.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: powder from white to light yellow, without visible impurities, readily soluble in water; the solution is clear, from colorless to light yellow, with pH 4–6.

Pharmacotherapeutic group.

Antibacterial agents for systemic use. Cephalosporins.

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 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:

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 from 0.1 to 0.3 μg/mL), other β-hemolytic streptococci (groups C, G, F), Streptococcus bovis (group D), Streptococcus viridans;

Gram-negative aerobes: Pseudomonas spp., including P. aeruginosa, P. putida, P. stutzeri; Escherichia coli, Klebsiella spp., including K. pneumoniae, K. 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 strains of enterococci 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 presented in the table.

Average plasma concentrations of cefepime (μg/mL)

Cefepime is less than 19% bound to plasma proteins, and binding does not depend on the drug concentration in blood serum. It poorly penetrates the intact blood-brain barrier. However, during meningitis, therapeutic concentrations are achieved in cerebrospinal fluid. High concentrations are found in urine, bile, peritoneal fluid, bronchial secretions, and tissues of the gallbladder, appendix, and prostate gland. 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 by glomerular filtration (total clearance of cefepime is approximately 120 mL/min, with mean renal clearance of 110 mL/min). Approximately 85% of the administered dose is excreted unchanged in urine, along with 1% of N-methylpyrrolidine, approximately 6.8% of N-methylpyrrolidine oxide, and approximately 2.5% of the cefepime epimer. The mean elimination half-life is approximately 2 hours. In volunteers who received doses up to 2 g intravenously every 8 hours for 9 days, no drug accumulation was observed.

Dose adjustment 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 is prolonged. The average half-life of cefepime during hemodialysis is 13 hours and during peritoneal dialysis is 19 hours.

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

Clinical characteristics.

Indications.

Adults.

Infections caused by cefepime-sensitive microorganisms, namely:

• respiratory tract infections (including hospital-acquired and community-acquired pneumonia, acute bronchitis, and exacerbations of chronic bronchitis);
• skin and soft tissue infections;
• intra-abdominal infections (including peritonitis and biliary tract infections);
• gynecological infections;
• septicemia.

Empirical therapy in patients with febrile neutropenia.

Prophylaxis of postoperative complications in intra-abdominal surgery.

Children.

• Pneumonia;
• urinary tract infections (both complicated, e.g. pyelonephritis, and uncomplicated);
• skin and soft tissue infections;
• septicemia;
• 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 solution; 5% and 10% glucose injection solution; 6M sodium lactate injection solution; 5% glucose and 0.9% sodium chloride injection solution; Ringer's lactate solution with 5% glucose injection solution.

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 nephron necrosis. Concurrent administration of cefepime and aminoglycosides increases the risk of ototoxic effects of the latter.

Effect on laboratory test results.

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

Special precautions for use.

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 to medicinal products. If an allergic reaction occurs, the drug should be discontinued immediately. Severe hypersensitivity reactions may require administration of epinephrine, hydrocortisone, antihistamines, and other emergency measures.

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

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

Dose adjustment of cefepime is not required in 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, caution should be exercised when selecting the dose, and renal function should be monitored routinely.

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

Prothrombin time should be monitored.

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 serum antibiotic concentrations may occur at standard doses in patients with renal impairment or other conditions that may worsen 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 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 most frequently observed in patients with renal impairment who received doses exceeding the recommended regimen, and in elderly patients with renal impairment receiving recommended doses of cefepime. Some cases occurred in patients who received doses adjusted according to their 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 is not required in such patients.

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

Administration of antibacterial agents alters the normal flora of the colon and may lead to overgrowth of Clostridium species. Studies indicate that the toxin produced by Clostridium difficile is the primary cause of antibiotic-associated colitis. After confirmation of pseudomembranous colitis, appropriate therapeutic measures should be initiated. Mild to moderate cases of pseudomembranous colitis may resolve after discontinuation of the drug. In moderate to severe cases, administration of fluids and electrolytes, protein supplementation, and use of 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. Repeated evaluation of the patient's condition is necessary. If superinfection develops, appropriate therapeutic measures should be initiated.

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

During cefepime therapy, positive results may be obtained in the direct Coombs' test. When performing hematological or transfusion procedures involving cross-matching blood or during Coombs' testing in newborns whose mothers received cephalosporin antibiotics before delivery, it should be considered that a positive Coombs' test may be due to the drug's administration.

When lidocaine is used as a solvent for pediatric administration, 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.

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

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

Ability to affect reaction speed when driving or operating machinery.

Not studied. If dizziness or other adverse reactions that may impair reaction speed occur, patients should refrain from driving or operating machinery.

Administration and Dosage.

The medication is intended for parenteral administration. The physician determines the dosage individually depending on the severity of the disease, patient's age, site of infection, and renal function.

The usual dosage for adults and children with a body weight over 40 kg is 1 g intravenously or intramuscularly every 12 hours. The usual duration of treatment is 7–10 days. Severe infections may require prolonged treatment. Dosage recommendations for cefepime in adults are provided in the table.

For prevention of infections during surgical procedures.
Administer 2 g of the drug intravenously over 30 minutes to adults, 60 minutes before the start of surgery. After completion, 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 (more than 12 hours) surgical procedures, repeat administration of an equivalent dose of cefepime is recommended 12 hours after the first dose, followed by administration of metronidazole.

Renal function impairment. In patients with impaired renal function (creatinine clearance less than 30 mL/min), the dose of the drug must be adjusted.

Recommended doses of cefepime for adults

If only serum creatinine concentration is known, 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 drug dose is removed 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 (CAPD), the drug may be used 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.

Children aged 1–2 months should receive the drug only for life-threatening indications. The condition of children weighing less than 40 kg receiving cefepime therapy should be monitored closely.

For children with impaired renal function, dosage reduction or increased dosing intervals 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 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 for 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.

Children weighing 40 kg or more should receive cefepime as in adults.

Administration of the drug. Cefepime 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 solution for injection, or 0.9% sodium chloride solution, as specified in the table below. It should be administered intravenously by slow injection over 3–5 minutes or via an intravenous infusion system.

Intramuscular administration. Cefepime can be dissolved in 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, or 0.5% or 1% lidocaine hydrochloride solution, at the concentrations specified in the table below.

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

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

Children.

May be used in children aged 1 month and older.

Overdose.

Symptoms: In cases of significant exceeding the recommended doses, 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 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 adrenaline and other forms of intensive therapy.

Adverse reactions.

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

Skin and subcutaneous tissue disorders: skin rashes, erythema, pruritus, urticaria.

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

Hepatobiliary disorders: hepatitis, cholestatic jaundice.

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: increased body temperature, sweating, chest/back pain, asthenia, injection site reactions including inflammation, phlebitis, pain.

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

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

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

Renal and urinary system disorders: renal failure.

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

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

In addition to the above-mentioned adverse reactions, adverse effects typical for cephalosporin antibiotics may occur: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhages, liver function disorders, cholestasis, pancytopenia.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging, out of reach of 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 for 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 types of interactions".

Packaging.

Vial containing 1 g of powder for injection solution, in cardboard pack №1, 5 such packs in a cardboard box №5.

Prescription category.

Prescription only.

Manufacturer. Sunc Labs Pvt. Ltd.

Manufacturer's address and place of business.

VI/51B, P.O. No. 2, Kothuvally, Pala, Kottayam – 686 573, Kerala, India.

Marketing Authorization Holder. Alembic Pharmaceuticals Limited, India.