Efipim®

INSTRUCTION for medical use of the medicinal product EFIPIME® (EFIPIME)

Composition:

Active substance: cefepime;

1 vial contains cefepime hydrochloride Ph. Eur. calculated as cefepime 1 g (sterile mixture of cefepime hydrochloride and arginine);

Excipient: arginine.

Pharmaceutical form. Powder for injection.

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

Pharmacotherapeutic group. Antibacterials 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 both Gram-positive and Gram-negative bacteria, including most strains resistant to aminoglycosides or third-generation cephalosporin antibiotics. Cefepime inhibits the synthesis of enzymes involved in the bacterial cell wall formation. The drug is highly resistant to hydrolysis by β-lactamases, has low affinity for chromosomally encoded β-lactamases, and rapidly penetrates into 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 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, 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 (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 spp. (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 below.

Average plasma concentrations of cefepime (mcg/mL)

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 inflammation of the meninges, it reaches therapeutic concentrations in the cerebrospinal fluid. Significant 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 from 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, average renal clearance is 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 epimer of cefepime. The elimination half-life averages 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 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 is prolonged. 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 required for such patients.

Clinical characteristics.

Indications.

Adults.

Infections caused by microorganisms sensitive to the drug:

• respiratory tract infections, including pneumonia and 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, including pyelonephritis;
• skin and soft tissue infections;
• septicemia;
• empirical therapy in patients with febrile neutropenia;
• bacterial meningitis.

Contraindications.

Hypersensitivity to any component of the drug or to cephalosporins, penicillins, and other β-lactam antibiotics.

Interaction with other medicinal products and other forms 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; 6M 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 given separately.

Diuretics (such as furosemide) and aminoglycosides reduce tubular secretion of cefepime, increase its serum concentration, prolong elimination half-life, enhance nephrotoxicity, and increase the risk of nephrotoxicity. 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 urine tests when using Benedict’s reagent. It is recommended to use glucose tests based on the enzymatic glucose oxidase reaction.

Special precautions.

It is necessary to clearly determine 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, administration of the drug should be discontinued. Severe hypersensitivity reactions may require administration of epinephrine, hydrocortisone, antihistamines, and other emergency measures.

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

In 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.

For patients aged 65 years and older with normal renal function, dose adjustment of cefepime is not required, 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.

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

Prothrombin time should be monitored.

The dose of the drug should be adjusted in patients with impaired renal function (creatinine clearance < 60 mL/min) to compensate for reduced renal elimination. Since prolonged antibiotic serum concentrations may occur at usual 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 altered 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 receiving doses adjusted according to their renal function. In most cases, symptoms of nephrotoxicity were reversible and resolved after discontinuation of cefepime and/or after hemodialysis.

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

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

Administration of antibacterial agents alters the normal flora of the colon and may lead to overgrowth of Clostridia. 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. Cases of mild to moderate pseudomembranous colitis may resolve after discontinuation of the drug. In moderate to severe cases, the need for fluid and electrolyte replacement, protein supplementation, and administration 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 developing bacteria resistant to this drug. Prolonged use of cefepime (as with other antibiotics) may lead to the development of superinfection. The patient's condition should be re-evaluated periodically. 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, 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 treatment with cefepime, positive results in the direct Coombs' test may be obtained. When performing hematological or transfusion procedures involving blood group determination by the cross-matching method, when performing the antiglobulin test, 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 administration of the drug.

When using lidocaine as a solvent in children, 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 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 small amounts in breast milk; 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 affect reaction speed occur, patients should refrain from driving or operating machinery.

Method of administration and dosage.

The drug is intended for parenteral administration. Prior to administration, a skin test for tolerance is recommended. The physician determines the dose 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 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 prolonged treatment. Dosage recommendations for cefepime in adults are presented in the table.

For prevention of infections during surgical procedures. Administer 2 g of the drug intravenously over 30 minutes, 60 minutes before the start of surgical operation in adults. After completion, additionally administer 500 mg 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 (over 12 hours), a repeat dose of cefepime equal to the initial dose 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 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) = 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 supplemental 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.

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

In pediatric patients with impaired renal function, dose reduction or increased 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:
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 children 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.

Children weighing 40 kg or more should receive cefepime as recommended for 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 injection, or 0.9% sodium chloride injection, as specified in the table below. Administer intravenously slowly 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 injection, 5% dextrose 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 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 the refrigerator (2–8 °C).

Children.

Can be administered to 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 epinephrine and other forms of intensive therapy.

Adverse Reactions

Immune system side effects: 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 sensations.

Hepatobiliary disorders: hepatitis, cholestatic jaundice.

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

General disorders and administration site conditions: increased body temperature, sweating, chest/back pain, asthenia, changes at the injection site including inflammation, phlebitis, pain.

Infections: candidiasis, vaginitis, genital pruritus, 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 disorders: renal failure.

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

Laboratory abnormalities: 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; false-positive urine glucose test.

In addition to the above-mentioned adverse reactions, other side effects characteristic of 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.

2 years.

Storage conditions.

Store the powder at a temperature not exceeding 25 °C in the original packaging, in a place inaccessible to children.

Incompatibility.

The drug should not be mixed in the same container with other medicinal products except for the diluents specified in the section “Dosage and Administration”.

Packaging. 1 g of the drug in a vial; 1 vial per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Astral SteriTech Private Limited.

Manufacturer’s address and place of business.

911, GIDC, Makarpura, Vadodara, Gujarat, 390010, India (IND)

Marketing Authorization Holder.

Orchid Pharma Limited.

Address of the Marketing Authorization Holder.

Orchid Towers, 313, Valluvar Kottam High Road, Nungambakkam, Chennai – 600 034, India.