Extencef

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

Composition:

Active substance: cefepime;

1 vial contains *cefepime hydrochloride equivalent to cefepime 500 mg or 1000 mg.

*Sterile mixture of cefepime hydrochloride and L-arginine.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical characteristics: powder from white to light yellow color.

Pharmacotherapeutic group. Antimicrobial agents for systemic use. Other β-lactam antibiotics. Fourth-generation cephalosporins. Cefepime. ATC code J01D E01.

Pharmacological Properties.

Pharmacodynamics.

Cefepime inhibits the synthesis of enzymes of 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 strains producing β-lactamase); other staphylococcal strains, including S. hominis, S. saprophyticus; Streptococcus pyogenes (Group A streptococci); Streptococcus agalactiae (Group B streptococci); Streptococcus pneumoniae (including strains with intermediate penicillin resistance — minimal inhibitory concentration from 0.1 to 1 mcg/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. agglomeratus, 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); Neisseria meningitidis; Pantoea agglomerans (formerly known as Enterobacter agglomerans); Providencia spp. (including P. rettgeri, P. stuartii); Salmonella spp.; Serratia spp. (including S. marcescens, S. liquefaciens); Shigella spp.; Yersinia enterocolitica.

(Cefepime is inactive against many strains of Xanthomonas maltophilia and Pseudomonas maltophilia.)

Anaerobes: Bacteroides spp., B. melaninogenicus belonging to Bacteroides; Clostridium perfringens; Fusobacterium spp.; Mobiluncus spp.; Peptostreptococcus spp.; Veillonella spp. (Cefepime is inactive against Bacteroides fragilis and Clostridium difficile.)

Pharmacokinetics.

Mean plasma concentrations of cefepime at various time points after single intravenous and intramuscular administration are presented in the table below.

Plasma concentrations of cefepime (mcg/mL) following intravenous (IV) and intramuscular (IM) administration.

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 individuals receiving 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 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 cefepime epimer. Protein binding of cefepime to plasma proteins is less than 19% and is independent of drug concentration in serum.

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.

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 is not required for these patients.

When a dose of cefepime 50 mg/kg every 12 hours was administered, no drug accumulation was observed, whereas the maximum plasma concentration, area under the curve, and half-life increased by approximately 15% at steady state when administered according to the regimen of 50 mg/kg every 8 hours.

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.

Prevention 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 cefepime or L-arginine, as well as to cephalosporin-class antibiotics, penicillins, or other β-lactam antibiotics.

Interaction with other medicinal products and other types of interactions.

When administering high doses of aminoglycosides concomitantly with Extencef, renal function should be closely monitored due to the potential nephrotoxicity and ototoxicity of aminoglycoside antibiotics. Nephrotoxicity has been observed after concomitant administration of other cephalosporins with diuretics such as furosemide.

Extencef at concentrations from 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, solutions of Extencef (as with most other β-lactam antibiotics) should not be administered simultaneously with metronidazole, vancomycin, gentamicin, tobramycin sulfate, or netilmicin sulfate solutions. If Extencef is prescribed together with these agents, each antibiotic should be administered separately.

Effect on laboratory test results.

Administration of cefepime may result in false-positive urine glucose tests when using Benedict's reagent. Enzymatic glucose-oxidation-based tests for glucose are recommended.

Special precautions for use.

For patients at high risk of severe infections (e.g., patients undergoing bone marrow transplantation with impaired marrow function due to severe progressive hematologic malignancy and profound 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 cautiously to all patients with any history of allergies, especially drug allergies. If an allergic reaction occurs, the drug should be discontinued immediately. Severe immediate-type hypersensitivity reactions may require administration of epinephrine and other supportive therapies.

Use with caution in patients with gastrointestinal disorders (particularly in medical history), especially colitis.

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 with Extencef. Evidence suggests that the toxin produced by Clostridium difficile is the primary cause of antibiotic-associated colitis. Once pseudomembranous colitis is confirmed, appropriate therapeutic measures should be initiated. Mild to moderate pseudomembranous colitis may resolve after discontinuation of the drug. In cases of moderate to severe colitis, consideration should be given to fluid and electrolyte replacement, protein supplementation, and administration of an antibacterial agent effective against Clostridium difficile.

Dosage adjustment of cefepime is required in patients with impaired renal function (creatinine clearance ≤ 60 mL/min) to compensate for reduced renal elimination. Because standard doses of cefepime may lead to increased antibiotic exposure in patients with renal impairment or other conditions that may compromise renal function, the maintenance dose of cefepime should be reduced in such patients. The next dose of cefepime should be determined based on the degree of renal impairment, severity of infection, and microbial susceptibility to the antibiotic. During post-marketing surveillance of cefepime products, severe, life-threatening, or fatal adverse events have been reported, including encephalopathy (altered mental status, including confusion, hallucinations, stupor, and coma), myoclonia, and seizures. Most cases occurred in patients with impaired renal function who received cefepime doses exceeding the recommended levels. However, severe reactions have occasionally occurred in patients receiving doses adjusted according to renal function. In most cases, symptoms of neurotoxicity were reversible and resolved after discontinuation of cefepime and/or after hemodialysis.

Warnings.

It is unlikely that prescribing cefepime in the absence of proven or suspected bacterial infection or for prophylactic use (except for prevention of postoperative complications) will be beneficial. Such use increases the risk of emergence of bacteria resistant to this medicinal product. Prolonged use of cefepime (as with other antibiotics) may lead to superinfection. The patient's condition should be re-evaluated regularly. If superinfection develops, appropriate measures should be taken.

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

During cefepime therapy, positive results in the direct Coombs test may occur. When performing hematological or transfusion procedures involving cross-matching blood using the antiglobulin test, 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 administration.

It has been demonstrated that L-arginine alters glucose metabolism and simultaneously increases serum potassium levels when administered at doses 33 times higher than the maximum recommended dose of cefepime. Effects at lower doses are currently unknown.

When lidocaine is used as a solvent, the safety information regarding lidocaine should be taken into account.

Use during pregnancy or breastfeeding.

Adequate and well-controlled studies in pregnant women have not been conducted; therefore, Extencef should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Cefepime is excreted in very small amounts into breast milk; therefore, breastfeeding should be discontinued during treatment with Extencef.

Effect on the ability to drive or operate machinery.

The effect of cefepime on the ability to drive or operate machinery has not been studied. However, it should be considered that adverse reactions affecting the nervous system may occur during treatment.

Administration and Dosage

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 prolonged treatment.

Dosage and route of administration vary depending on the sensitivity of the causative microorganisms, the severity of the infection, and the patient's renal function. Dosage recommendations for the drug Extencef in adults are provided in the table.

For prevention of infections during surgical procedures. 2 g of the drug should be administered intravenously over 30 minutes to adults 60 minutes before the start of surgery. After completion, an additional 500 mg of metronidazole should be administered intravenously. Metronidazole solutions should not be administered simultaneously with Extencef. The infusion system should be flushed before administration of metronidazole.

During prolonged surgical procedures (lasting more than 12 hours), a repeat dose of Extencef should be administered 12 hours after the initial dose, followed by administration of metronidazole.

Renal function impairment. The dose of Extencef should be adjusted in patients with impaired renal function (creatinine clearance less than 30 mL/min).

* On the day of dialysis, the injection should be administered after the dialysis session.

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

Men:

Women:

Creatinine clearance (ml/min) = the above value × 0.85.

During hemodialysis, approximately 68% of the drug dose is eliminated from the body over a 3-hour period. After each dialysis session, a supplemental dose equal to the initial dose should be administered. For continuous ambulatory peritoneal dialysis (CAPD), the drug can be administered at the initial standard recommended doses of 500 mg, 1 g, or 2 g, depending on the severity of infection, every 48 hours.

Children aged 1 to 2 months:
Extencef 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 with body weight below 40 kg receiving Extencef therapy must be closely monitored.

Children aged 2 months and older:
The maximum dose in pediatric patients should not exceed the recommended adult dose. The usual recommended dose for children weighing less than 40 kg in 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 for febrile neutropenia and bacterial meningitis).

The usual duration of treatment is 7–10 days; severe infections may require longer therapy. Children weighing 40 kg or more should receive Extencef in the same manner as adults.

In children with impaired renal function, dose reduction or increased dosing intervals are recommended.

Calculation of creatinine clearance in children:

or

Administration of the drug. Extencef can be administered intravenously (over 3−5 minutes to 30 minutes) 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, Extencef should be dissolved in sterile water for injections, 5 % glucose for injections, or 0.9 % sodium chloride solution for injections, as indicated in the table below. Administer intravenously slowly over 3−5 minutes or via an intravenous infusion system.

Intramuscular administration. Extencef can be dissolved in sterile water for injections, 0.9 % sodium chloride solution for injections, 5 % glucose solution for injections, bacteriostatic water for injections with parabens or benzyl alcohol, or 0.5 % or 1 % lidocaine hydrochloride solution, at the concentrations specified in the table below.

When using lidocaine as a solvent, a skin test for tolerance should be performed prior to administration, and safety information regarding lidocaine must be taken into account.

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

Appropriate microbiological investigations should be carried out to identify the causative microorganism(s) and determine susceptibility to cefepime. However, Extencef may be used as monotherapy prior to identification of the causative microorganism, because it has a broad spectrum of antibacterial activity against both gram-positive and gram-negative microorganisms. In patients at risk of mixed aerobic/anaerobic (including Bacteroides fragilis) infections, treatment with Extencef in combination with an agent active against anaerobes may be initiated before identification of the causative pathogen.

Reconstituted solutions for intramuscular and intravenous injections are stable for use for 24 hours at room temperature or for 7 days if stored in a refrigerator (2−8 °C).

Children.

May be administered to children aged 1 month and older.

Overdose.

Symptoms: In cases of significant overdose, adverse reactions are intensified, especially in patients with impaired renal function. 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 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

Infections and infestations: Vaginitis, oral candidiasis, vaginal candidiasis;

Central nervous system disorders: Headache, dizziness, insomnia, paresthesia, restlessness, seizures, myoclonus, epileptiform seizures, altered consciousness, encephalopathy (loss of consciousness, hallucinations, stupor, coma);

Cardiovascular system disorders: Vasodilation, chest pain, tachycardia, hemorrhage;

Gastrointestinal disorders: Nausea, vomiting, diarrhea, abdominal pain, constipation, dyspepsia, colitis (including pseudomembranous colitis);

Respiratory system disorders: Cough, respiratory disorders, dyspnea, sore throat;

Genitourinary system disorders: Genital pruritus, renal failure, toxic nephropathy, renal dysfunction;

Immune system disorders: Hypersensitivity reactions, including anaphylaxis, anaphylactic shock, angioneurotic edema;

Skin and subcutaneous tissue disorders: Pruritus, rash, urticaria, erythema, Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis;

Blood and lymphatic system disorders: Neutropenia, agranulocytosis, transient leukopenia, thrombocytopenia, aplastic anemia, hemolytic anemia, eosinophilia, pancytopenia, hemorrhages;

Hepatobiliary disorders: Hepatitis, liver function abnormalities, cholestasis, cholestatic jaundice;

Reactions at the site of administration: Local reactions, including phlebitis and inflammation with intravenous administration; pain and/or inflammation at the injection site with intramuscular administration;

Other: Peripheral skin edema, altered taste sensation, asthenia, fever, sweating, back pain;

Laboratory test abnormalities: Increased levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin; prolonged prothrombin time or partial thromboplastin time (PTT), and positive Coombs test without hemolysis, decreased phosphorus levels, hypocalcemia (more common in elderly patients). There are no reports regarding clinical consequences of changes in calcium or phosphorus levels. Transient increases in blood urea nitrogen and/or serum creatinine; anemia, eosinophilia, agranulocytosis, transient thrombocytopenia, elevated calcium levels. Transient leukopenia and neutropenia, decreased hematocrit have also been observed.

Shelf life.

2 years.

Storage conditions.

Store in a light-protected place at a temperature not exceeding 25 °C.

Keep out of reach of children.

Incompatibility.

Do not mix with other medicinal products in the same container.

Use only the solvents specified in the section "Method of administration and dosage."

Packaging.

500 mg or 1000 mg of the drug in a glass vial stoppered with a rubber plug and sealed with an aluminum crimp cap equipped with a flip-off cap ensuring first-opening control.

1 vial per cardboard box.

Prescription category.

Prescription only.

Manufacturer.

Astral SteriTech Private Limited
Astral steritech Private Limited

Manufacturer's address and place of business.

911, G.I.D.C., Makarpura, Vadodara, Gujarat, 390 010, India
911, Gidc, Makarpura, Vadodara, Gujarat 390 010, India (IND)

Marketing Authorization Holder.

M. Biotech Ltd
M. Biotech ltd

Address of the Marketing Authorization Holder.

Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom