Exipim

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EXIPIME (Exipime®)

Composition:

Active substance: cefepime;

One vial contains cefepime hydrochloride equivalent to 500 mg, 1000 mg, or 2000 mg of cefepime;

Excipient: arginine.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: sterile powder, white to light yellow in color, without visible impurities; the powder solution should be clear, colorless to light yellow; pH of the solution - 4–6.

Pharmacotherapeutic group.

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

ATC code J01DE01.

Pharmacological Properties

Pharmacodynamics

Cefepime inhibits the synthesis of enzymes in the bacterial cell wall 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 resistance to penicillin — MIC from 0.1 to 1 μg/mL); other β-hemolytic streptococci (Groups C, G, F); S. bovis (Group D); Viridans group streptococci. (Most 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
The mean plasma concentrations of cefepime in healthy adult males at various time points after single intravenous and intramuscular administration are shown in Table 4.

Plasma concentrations of cefepime (μg/mL) after intravenous (IV) and intramuscular (IM) administration

Table 4

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

The average elimination half-life of cefepime is approximately 2 hours. In healthy volunteers who received 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 the N-methylpyrrolidine oxide. The average total clearance is 120 mL/min. Cefepime is eliminated almost exclusively by renal mechanisms, primarily via glomerular filtration (average renal clearance is 110 mL/min). Approximately 85% of the administered dose is excreted in urine as unchanged cefepime, 1% as N-methylpyrrolidine, about 6.8% as N-methylpyrrolidine oxide, and about 2.5% as the epimer of cefepime. 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. The average 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 impairment or cystic fibrosis are not altered. Dose adjustment in such patients is not required.

The recommended dose of the drug is 50 mg/kg body weight administered intravenously over 5 to 20 minutes every 8 hours.

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;
• 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 antibiotics of the cephalosporin class, penicillins or other β-lactam antibiotics.

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 of 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 (as with 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 agents, each antibiotic should be administered separately.

Special precautions for use.

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

It is essential to determine carefully 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 type of allergy, particularly to medicinal products. If an allergic reaction occurs, the drug should be discontinued. Severe immediate-type hypersensitivity reactions may require administration of epinephrine and other forms of intensive therapy.

Cases of pseudomembranous colitis have been reported with the use of nearly all broad-spectrum antibiotics. Therefore, it is important to consider the possibility of this condition in patients who develop diarrhea during treatment. Mild cases of colitis may resolve upon discontinuation of the drug; moderate to severe cases may require specific therapeutic intervention.

The onset of diarrhea may indicate pseudomembranous colitis, the diagnosis of which is based on colonoscopic findings. This condition requires immediate discontinuation of treatment and initiation of appropriate specific therapy.

Since renal function declines with age, dosage for elderly patients should be adjusted according to the renal function status of each individual patient.

Dosage adjustment is not required in patients with normal renal function. Renal function should be monitored when cefepime is used concomitantly with potentially nephrotoxic antibiotics (particularly aminoglycosides) and potent diuretics.

Cephalosporins may be absorbed on the surface of erythrocytes and react with antibodies directed against the drugs, resulting in a positive Coombs' test. A positive Coombs' test has been reported in patients receiving cefepime twice daily, in the absence of signs of hemolysis.

When testing urine for glucosuria, false-positive results may occur; therefore, glucose in urine should be determined by glucose oxidase methods during cefepime therapy.

As with other antibiotics, cefepime use may lead to overgrowth of resistant microorganisms. If superinfections develop during treatment, appropriate measures should be taken.

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 potential benefit to the mother outweighs the potential risk to the fetus.

Cefepime is excreted in human milk in very small amounts; therefore, breastfeeding should be discontinued during treatment with the drug.

Ability to affect reaction rate while driving or operating machinery.

Not studied.

Dosage and administration.

Before using the drug, a skin sensitivity test should be performed.

The usual dose for adults 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.

However, dosage and route of administration vary depending on the susceptibility of the causative microorganisms, severity of the infection, and the patient's renal function.

Dosage recommendations for adults are provided in Table 1.

Table 1

For prophylaxis of infection development during surgical procedures. Administer 2 g of the drug intravenously over 30 minutes to adults, 60 minutes before the start of surgical operation. 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 metronidazole administration.

During prolonged (over 12 hours) surgical procedures, repeat administration of an equal dose of the drug is recommended 12 hours after the first dose, followed by metronidazole administration.

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

Recommended cefepime doses for adults Table 2

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

Men:

creatinine clearance (mL/min) = ;

Women:

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

During hemodialysis, approximately 68% of the drug dose is eliminated from the body over 3 hours. After each dialysis session, a supplementary dose equal to the initial dose should be administered. For continuous ambulatory peritoneal dialysis (CAPD), 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.

The drug should be prescribed to children aged 1–2 months only for life-threatening indications. Children with body weight below 40 kg receiving cefepime should be closely monitored.

For children with impaired renal function, a reduced dose or prolonged dosing interval is recommended.

Calculation of creatinine clearance in children:

creatinine clearance (mL/min/1.73 m²) =

or

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

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 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 3. It should be administered intravenously slowly over 3–5 minutes or via an intravenous infusion system.

Intramuscular administration. The drug can 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 indicated in Table 3 below.

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

Table 3

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

To identify the causative microorganism(s) and determine susceptibility to cefepime, appropriate microbiological investigations should be performed. However, cefepime may be used as monotherapy before identification of the causative microorganism, due to its broad spectrum of antibacterial activity against Gram-positive and Gram-negative microorganisms. In patients at risk of mixed aerobic/anaerobic (including Bacteroides fragilis) infections, treatment with cefepime in combination with an agent active against anaerobes may be initiated before identification of the causative organism.

Children.

May be administered to children aged 1 month and older.

Overdose.

Symptoms. In cases 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 the 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.

Side effects.

Hypersensitivity: itching, urticaria, anaphylaxis.

Gastrointestinal tract: nausea, vomiting, oral candidiasis, diarrhea, colitis (including pseudomembranous colitis), abdominal pain, constipation.

Nervous system: headache, epileptiform seizures, dizziness, paresthesia.

Other: fever, vaginitis, erythema, vasodilation, respiratory disorders, genital itching, candidiasis.

Local reactions at the site of administration:
Intravenous administration – phlebitis and inflammation;
Intramuscular administration – pain, inflammation.

Post-marketing studies:

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

Laboratory findings: increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), 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.

Blood and lymphatic system disorders: hyper-eosinophilia, neutropenia, thrombocytopenia, prolonged prothrombin time and activated partial thromboplastin time, arterial hypotension, vasodilation, decreased serum phosphate concentration.

Immune system disorders: itching, urticaria, fever, severe anaphylaxis (anaphylactic shock).

Nervous system disorders: encephalitis, paresthesia (alterations in attention and consciousness may lead to coma, hallucinations, myoclonus, seizures), confusion, dizziness, seizures, dysgeusia, tinnitus, and/or severe renal failure, which most commonly occurs in patients with impaired renal function when recommended doses are exceeded, particularly in elderly patients. Symptoms of neurotoxicity are usually reversible and resolve after discontinuation of the drug and/or hemodialysis.

Skin and subcutaneous tissue disorders: rash.

Gastrointestinal disorders: diarrhea, nausea, vomiting, stomatitis, abdominal pain, colitis, particularly pseudomembranous colitis, oral mucosal ulcers.

Hepatobiliary and biliary tract disorders: mild and transient elevation of transaminase levels (AST, ALT).

Musculoskeletal and connective tissue disorders: joint swelling and pain.

Reproductive system and breast disorders: vaginitis.

General disorders and administration site conditions: phlebitis and thrombophlebitis, pain and inflammation at the injection site.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging. Keep out of reach of children.

After reconstitution, do not freeze the solution.

After preparation, the solution for intramuscular administration may be stored for up to
12 hours at temperatures up to 25 °C and up to 7 days in the original packaging — in the refrigerator at 2–8 °C.

After preparation, the solution for intravenous administration may be stored for up to 24 hours at temperatures up to 25 °C and up to 5 days in the original packaging — in the refrigerator at 2–8 °C.

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

Incompatibility.

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

Packaging.

1 vial per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Exir Pharmaceutical Company, Iran.

Exir Pharmaceutical Company, Iran.

Manufacturer's address and place of business.

2nd Km Ring Road, Boroujerd 69189, Iran.

2nd Km Ring Road, Boroujerd 69189, Iran.