Pozineg

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

Composition:

Active substance: cefepime;

1 vial contains cefepime hydrochloride (equivalent to cefepime) – 1000 mg or 2000 mg;

Excipient: L-arginine.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white to pale yellow crystalline powder in a clear glass vial, stoppered with a grey rubber stopper and sealed with an aluminum flip-off cap, with an orange plastic cap (for the 1000 mg dose) or a green plastic cap (for the 2000 mg dose).

Pharmacotherapeutic group. Antimicrobial agents for systemic use. Other β-lactam antibiotics. 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 bactericidal action. It is active against both Gram-positive and Gram-negative bacteria, including most strains resistant to aminoglycosides or third-generation cephalosporins such as ceftazidime. Cefepime is highly stable against the effects of most β-lactamases and rapidly penetrates Gram-negative bacteria. The binding affinity of cefepime to penicillin-binding protein PBP 3 significantly exceeds that of other parenteral cephalosporins. Moderate affinity of cefepime to PBP 1a and 1b also contributes to its bactericidal activity. The MBC (minimum bactericidal concentration)/MIC (minimum inhibitory concentration) ratio for cefepime is less than 2 for more than 80% of isolates of all susceptible Gram-positive and Gram-negative bacteria.

Cefepime inhibits bacterial cell wall enzyme synthesis. The drug has low affinity for β-lactamases encoded by chromosomal genes.

Cefepime is active against the following microorganisms:

Gram-positive aerobes: Staphylococcus aureus (including β-lactamase-producing strains) and Staphylococcus epidermidis (including β-lactamase-producing strains); other staphylococcal strains (including S. hominis, S. saprophyticus); Streptococcus pyogenes (Group A); Streptococcus agalactiae (Group B); Streptococcus pneumoniae (including strains with intermediate penicillin resistance — MIC from 0.1 to 1 μg/mL); other β-hemolytic streptococci (Groups C, G, F); S. bovis (Group D); Viridans group streptococci (most Enterococcus strains, e.g., Enterococcus faecalis, and methicillin-resistant staphylococci, which 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 (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 catarrhalis (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.

Cefepime is inactive against many strains of Xanthomonas (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

Cefepime is completely absorbed after intramuscular administration.

Mean plasma concentrations of cefepime in healthy adult males at various time points after single intravenous and intramuscular administration are shown in Table 1.

Table 1

Plasma concentrations of cefepime (μg/mL) following intravenous (i.v.) and intramuscular (i.m.) 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 and does not depend on the dose within the range of 250 mg – 2 g. When administered intravenously at doses up to 2 g every 8 hours for 9 days, no drug accumulation was observed.

Cefepime is metabolized to N-methylpyrrolidine, which is rapidly converted into N-methylpyrrolidine oxide. Cefepime is primarily excreted via glomerular filtration (total clearance of cefepime is approximately 120 ml/min, mean hepatic clearance is 110 ml/min). Approximately 80–85% of the 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. Plasma protein binding of cefepime is less than 19% and does not depend on drug concentration in blood serum.

In patients aged 65 years and older with normal renal function, dosage adjustment is not required.

In patients with renal impairment, the elimination half-life of cefepime is prolonged, and a linear relationship is observed between total drug clearance and creatinine clearance. The half-life in patients with severe renal dysfunction requiring hemodialysis is 13 hours, and during continuous ambulatory peritoneal dialysis, it is 19 hours. In patients with abnormal renal function, the dose should be individually adjusted.

The pharmacokinetics of cefepime in patients with impaired liver function or cystic fibrosis does not change. Dosage adjustment in such patients is not required.

Children. Pharmacokinetic studies of cefepime were conducted in children aged 2 months to 11 years after single or multiple doses administered every 8 or every 12 hours. After a single intravenous injection, the mean total body clearance and steady-state volume of distribution were 3.3 (1.0) ml/min/kg and 0.3 (0.1) L/kg, respectively. The urinary excretion of unchanged cefepime was 60.4 (30.4)% of the administered dose, and the mean renal clearance was 2 (1.1) ml/min/kg. Patient age and sex did not significantly affect total body clearance or volume of distribution when corrected for body weight. When cefepime was administered at 50 mg/kg every 12 hours, no drug accumulation was observed, whereas with the regimen of 50 mg/kg every 8 hours, plasma maximum concentration, area under the curve, and half-life increased by approximately 15% at steady state. Cefepime exposure in children after intravenous administration of 50 mg/kg is similar to that in adults after intravenous administration of 2 g. After intravenous administration, the mean peak plasma concentration of cefepime at steady state was 68 mcg/ml, reached within 0.75 hours. Eight hours after intramuscular injection, the mean plasma concentration of cefepime was 6 mcg/ml. The absolute bioavailability of cefepime after intramuscular injection averaged 82%.

Due to the inability to identify the causative pathogen and determine its susceptibility to antibiotics, or due to lack of time, cefepime may be used as empirical therapy, as it has a broad spectrum of antibacterial activity. In patients at risk of mixed aerobic-anaerobic infections, treatment with cefepime may be initiated pending pathogen identification, in combination with an anti-anaerobic agent.

Indications.

Adults.

Infections caused by microorganisms susceptible 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 cefepime or L-arginine, as well as to cephalosporin antibiotics, penicillins, or other β-lactam antibiotics.

Interaction with other medicinal products and other forms of interactions.

When high doses of aminoglycosides are used 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 use of other cephalosporins with diuretics such as furosemide.

Cefepime 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; 6 M sodium lactate injection; 5% glucose and 0.9% sodium chloride injection; Ringer's lactate with 5% glucose injection.

To avoid potential drug interactions with other medicinal products, solutions of the drug Poseneg (like most other β-lactam antibiotics) should not be administered simultaneously with solutions of metronidazole, vancomycin, gentamicin, tobramycin sulfate, or netilmicin sulfate. If co-administration of Poseneg with these agents is necessary, each antibiotic should be administered separately.

Effect on laboratory test results.

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

Special precautions for use.

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

It is essential to determine precisely whether the patient has previously experienced immediate-type hypersensitivity reactions to cefepime or other β-lactam antibiotics. Antibiotics should be administered with caution to all patients with any type of allergy, particularly drug allergies. If an allergic reaction occurs, the drug must be discontinued immediately. Severe immediate-type hypersensitivity reactions may require treatment with adrenaline and other therapeutic measures.

Use with caution in patients with gastrointestinal disorders (particularly in those with a history of colitis).

Cases of pseudomembranous colitis have been reported with almost all broad-spectrum antibiotics. Therefore, it is important to consider the possibility of this condition in cases of diarrhea occurring during treatment with Zinacef. 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. Mild to moderate cases of pseudomembranous colitis may resolve after discontinuation of the drug. In moderate to severe cases, consideration should be given to administration of fluids and electrolytes, protein supplementation, and use of an antibacterial agent effective against Clostridium difficile.

In patients with impaired renal function (creatinine clearance ≤ 60 mL/min), the dose of cefepime must be adjusted to compensate for reduced renal elimination. Because prolonged serum antibiotic concentrations may occur when standard doses of cefepime are administered to patients with renal impairment or other conditions that may worsen renal function, the maintenance dose of cefepime should be reduced in such patients. The degree of renal impairment, severity of infection, and microbial susceptibility to the antibiotic should be taken into account when determining subsequent doses of cefepime. During post-marketing surveillance of cefepime-containing drugs, severe adverse events that were life-threatening or fatal have been reported: 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 ones. Some cases 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 hemodialysis.

Precautions.

It is unlikely that prescribing cefepime in the absence of proven or suspected bacterial infection, or for prophylactic use, will be beneficial; such use may increase the risk of emergence of bacteria resistant to this drug. Prolonged use of cefepime (as with other antibiotics) may lead to development of superinfection. Repeated patient evaluation is necessary. 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 liver or kidney function, malnourished patients, and those receiving prolonged courses of 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, including blood group determination by cross-matching, 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 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 still unknown.

Use during pregnancy or breastfeeding.

Cefepime may be administered during pregnancy only if the expected 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.

The effect of cefepime on reaction speed during driving or operating machinery has not been studied; however, it should be considered that adverse reactions affecting the nervous system may occur during treatment.

Dosage and Administration.

The usual dosage 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 may vary depending on the susceptibility of the causative microorganisms, the severity of the infection, and the patient's renal function. Dosage recommendations for the drug in adults are provided in Table 2.

Table 2

For prevention of infections during surgical procedures. 2 g of the drug is administered intravenously over 30 minutes to adults 60 minutes before the start of surgical intervention. At the end of this infusion, an additional 500 mg of metronidazole is administered intravenously. Metronidazole solutions should not be administered simultaneously with cefepime. The infusion system must be flushed before administration of metronidazole.

During prolonged surgical procedures (lasting more than 12 hours), a repeat dose of an equal amount of cefepime is recommended 12 hours after the first dose, followed by administration of metronidazole.

Renal function impairment. Cefepime is eliminated by the kidneys via glomerular filtration; therefore, the dose should be adjusted in patients with impaired renal function (creatinine clearance less than 30 mL/min) (Table 3).

Table 3

Recommended doses of cefepime for adults

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

If only the serum creatinine concentration is known, creatinine clearance can be calculated using the formula provided 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 administered 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 may be used 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.

Children aged 1 to 2 months. The drug 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 cefepime therapy must be closely monitored.

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 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 patients with febrile neutropenia or 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 cefepime doses as recommended for adults.

For children with impaired renal function, dose reduction or extended 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)

The drug can be administered via deep intramuscular injection (0.5 g and 1 g), slow intravenous injection, or infusion (from 3–5 minutes up to 30 minutes).

Intravenous administration. Cefepime should be dissolved in water for injection or any other compatible diluent at concentrations specified in Table 3. Solutions for intravenous administration may be administered directly into the vein by slow (3–5 minutes) injection through an intravenous line or directly into a compatible infusion solution (administered over 30 minutes).

For intravenous administration, cefepime is compatible with the following diluents: water for injection, 0.9% sodium chloride injection (with or without 5% dextrose); 5% and 10% dextrose injection; 1/6 M sodium lactate injection; lactated Ringer’s solution (with or without 5% dextrose).

Intramuscular administration. The drug may be reconstituted with water for injection, 0.9% sodium chloride injection, 5% dextrose injection, bacteriostatic water for injection with paraben or benzyl alcohol, or 0.5% or 1% lidocaine hydrochloride solution, at concentrations specified in Table 4.

When lidocaine is used as a diluent, a skin test for tolerance should be performed prior to administration.

Table 4

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

Appropriate microbiological investigations should be performed to identify the causative microorganism(s) and to determine susceptibility to cefepime. However, the drug may be used as monotherapy prior to identification of the causative microorganism, since 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 may be initiated in combination with an agent active against anaerobes, pending identification of the causative pathogen.

Children.

The drug is administered to children aged 1 month and older.

Overdose.

Symptoms. In cases of significant overdose, particularly in patients with impaired renal function, adverse effects may intensify. 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 the 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 disorders: hypersensitivity reactions, including anaphylaxis, anaphylactic shock, angioneurotic edema.

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

Cardiovascular system disorders: tachycardia, vasodilation.

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

Nervous system disorders: headache, insomnia, restlessness, convulsions, dizziness, paresthesia, epileptiform seizures, encephalopathies (loss of consciousness, hallucinations, stupor, coma), myoclonia.

Hepatobiliary system disorders: hepatitis, cholestatic jaundice.

Skin and subcutaneous tissue disorders: rash, pruritus, urticaria.

Other: asthenia, increased sweating, fever, vaginitis, erythema, chest pain, back pain, peripheral edema, genital pruritus, candidiasis, renal failure.

Local reactions at the site of administration:

Intravenous administration – phlebitis and inflammation;

Intramuscular administration – pain, inflammation.

Laboratory findings: increased levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin; anemia, eosinophilia, prolonged prothrombin time or partial thromboplastin time, and positive Coombs test without hemolysis. Transient increases in blood urea nitrogen and/or serum creatinine, transient leukopenia, neutropenia, agranulocytosis, transient thrombocytopenia.

Possible adverse reactions typical for cephalosporin antibiotics: 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 in a place inaccessible to children, at a temperature not exceeding 30 °C.

After reconstitution, the solution is stable for 24 hours at a temperature not exceeding 30 °C or for 7 days at 2–8 °C in a refrigerator.

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 of powder for solution for injection in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Aurobindo Pharma Limited, Unit-VI / Aurobindo Pharma Limited, Unit-VI

Manufacturer's address and location of manufacturing site.

Sy. No. 329/39 & Sy. No. 329/47, Chitkul Village, Patancheru Mandal, Sanga Reddy District, Telangana State, India.