Brodipim 1 g

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BROPIME 1 G BRODIPIME 1 GM

Composition:

Active substance: cefepime;

1 vial contains cefepime hydrochloride equivalent to cefepime 1000 mg;

Excipient: L-arginine.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: powder ranging from white to light yellow in color.

Pharmacotherapeutic group.

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

Pharmacological Properties

Pharmacodynamics

Brodipim 1 g is a β-lactam cephalosporin antibiotic of the fourth generation with a broad spectrum of activity 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 such as ceftazidime. Brodipim is highly resistant to the action of most β-lactamases and rapidly penetrates Gram-negative bacteria. The binding affinity of cefepime for penicillin-binding protein (PBP) significantly exceeds that of other parenteral cephalosporins. Moderate affinity of cefepime for PBPs 1a and 1b also contributes to its level of bactericidal activity. The MBC (minimum bactericidal concentration)/MIC 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 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 encoded β-lactamases, and rapidly penetrates Gram-negative bacterial cells.

Cefepime is active against the following microorganisms:

Gram-positive aerobes: Staphylococcus aureus, 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 penicillin resistance – minimum inhibitory concentration (MIC) 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. sakazakii), Proteus spp. (including P. mirabilis, P. vulgaris), Acinetobacter calcoaceticus subsp. 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; 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

Cefepime is completely absorbed after intramuscular injection.

Mean plasma concentrations of cefepime in healthy adult patients at various time points after single intravenous (i.v.) and intramuscular (i.m.) administration are shown in Table 1.

Mean plasma concentrations of cefepime (mcg/mL) following intravenous (i.v.)
and intramuscular (i.m.) administration

Table 1

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 is independent of dose within the range of 250 mg – 2 g. In healthy subjects 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 mean total clearance of cefepime is 120 mL/min.) Cefepime is eliminated almost exclusively by renal mechanisms—primarily via glomerular filtration (mean 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 cefepime epimer. Plasma protein binding of cefepime is less than 19% and does not depend on the drug concentration in blood serum.

Patients aged 65 years and older with normal renal function do not require dose adjustment, despite lower renal clearance compared to younger patients.

Studies conducted in patients with varying degrees of renal impairment have demonstrated an increased elimination half-life. On average, the half-life in patients with severe renal dysfunction requiring dialysis is 13 hours with hemodialysis and 19 hours with peritoneal dialysis. Dose adjustment in patients with impaired renal function should be individualized.

The pharmacokinetics of cefepime in patients with hepatic dysfunction or cystic fibrosis are not altered. Dose adjustment is not required for these patients.

Children

Pharmacokinetic studies of cefepime were conducted in children aged 2 months to 11 years after single or multiple intravenous doses administered every 8 or every 12 hours. After a single intravenous dose, mean total body clearance and steady-state volume of distribution averaged 3.3 (1.0) mL/min/kg and 0.3 (0.1) L/kg, respectively. Renal excretion of unchanged cefepime accounted for 60.4 (30.4)% of the administered dose, and mean renal clearance was 2 (1.1) mL/min/kg. Patient age and sex had no significant effect on total body clearance or volume of distribution when corrected for body weight. With a dosing regimen of 50 mg/kg every 12 hours, no drug accumulation was observed, whereas with dosing every 8 hours at 50 mg/kg, maximum plasma concentration, area under the curve, and elimination half-life increased by approximately 15% at steady state. Cefepime exposure in children after intravenous administration of 50 mg/kg is comparable to that observed in adults after intravenous administration of 2 g. After intravenous administration, mean steady-state maximum plasma concentration of cefepime was 68 µg/mL, achieved within 0.75 hours. Eight hours after intramuscular administration, the plasma concentration of cefepime averaged 6 µg/mL. Absolute bioavailability of cefepime after intramuscular injection averaged 82%.

Concentrations of the drug in cerebrospinal fluid (CSF) and plasma in children with bacterial meningitis

Table 2

* Age from 3.1 months to 12 years with a standard deviation in age of ± 3 years.

Drug dosage of 50 mg/kg body weight administered intravenously over 5–20 minutes every 8 hours. Plasma concentration and CSF levels were determined at the end of infusion on day 2 or 3 of treatment with the drug.

Clinical characteristics.

Indications.

• Lower respiratory tract infections, including pneumonia and bronchitis;
• urinary tract infections (both complicated, e.g. pyelonephritis, and uncomplicated);
• skin and soft tissue infections;
• intra-abdominal infections, including peritonitis and biliary tract infections;
• gynecological infections;
• sepsis;
• febrile neutropenia;
• bacterial meningitis.

Empirical therapy in patients with neutropenic fever.

Prevention of postoperative complications in intra-abdominal surgery.

Children

• Pneumonia;
• urinary tract infections, including pyelonephritis;
• skin and subcutaneous tissue infections;
• sepsis;
• empirical therapy in patients with neutropenic fever;
• bacterial meningitis.

Contraindications.

The drug is contraindicated in patients with hypersensitivity reactions to cefepime or to 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 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 following concomitant administration 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; 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 (like 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.

Effect on laboratory test results.

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

Special precautions.

For 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 hematologic disorders), monotherapy may be insufficient, and combination antimicrobial therapy is indicated.

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 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 therapeutic interventions.

Cases of pseudomembranous colitis have been reported with the use of nearly all broad-spectrum antibiotics. Therefore, pseudomembranous colitis must be considered in the differential diagnosis whenever diarrhea occurs during cefepime therapy. The condition may range from mild diarrhea to fatal colitis. Mild cases of colitis may resolve upon discontinuation of the drug; moderate to severe cases may require specific treatment.

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

A skin sensitivity test must be performed prior to administration.

During prolonged treatment, regular monitoring of liver, kidney, and hematopoietic system function is required.

Dose adjustment of cefepime is necessary in patients with impaired renal function (creatinine clearance < 60 mL/min) to compensate for reduced renal elimination. Prolonged elevated serum antibiotic concentrations may occur at standard doses in patients with renal impairment or other conditions that may compromise renal function; therefore, 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 subsequent dosing.

Serious adverse reactions, including reversible encephalopathy (confusion, including altered consciousness), myoclonia, seizures, and/or renal failure, have been observed most frequently in patients with renal impairment receiving doses exceeding the recommended dose, and in elderly patients with renal impairment receiving recommended doses of cefepime. Some cases have occurred in patients receiving doses adjusted according to 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.

Antibacterial agents alter the normal flora of the colon and may promote overgrowth of Clostridium species. Studies indicate that the toxin produced by Clostridium difficile is the primary cause of antibiotic-associated colitis. Once pseudomembranous colitis is diagnosed, 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.

Warnings.

It is unlikely that prescribing cefepime in the absence of proven or suspected bacterial infection, or for prophylactic use, will be beneficial, and 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 superinfection. Patients 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 receiving prolonged courses of antimicrobial therapy. Prothrombin levels should be monitored in high-risk patients, and vitamin K should be administered if necessary.

Positive results in the direct Coombs' test may occur during cefepime therapy. When performing hematological or transfusion procedures involving the antiglobulin test or 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.

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 potassium levels when administered at doses 33 times higher than the maximum recommended dose of cefepime. Effects at lower doses are currently unknown.

As with other antibiotics, cefepime use may lead to colonization with resistant microorganisms. Appropriate measures should be taken if superinfection develops during treatment.

Environmental release of the medicinal product should be minimized. Disposal of the drug into sewage systems or household waste should be avoided.

Use during pregnancy or breastfeeding.

Animal studies have shown no effect on reproductive function and no adverse effects on the fetus. However, adequate and well-controlled studies in pregnant women have not been conducted. Therefore, cefepime should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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

Ability to affect reaction speed when operating vehicles or machinery.

Since adverse reactions affecting the central nervous system may occur during treatment, patients should refrain from driving vehicles or operating machinery.

Administration and Dosage

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 therapy.

However, the dosage and route of administration should be adjusted according to the sensitivity of the causative microorganisms, the severity of the infection, and the patient's renal function. Dosage recommendations for Brodipime 1 g in adults are provided in Table 3.

Table 3

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 surgery. After completion, an additional 500 mg of metronidazole should be administered intravenously. Metronidazole solutions should not be administered simultaneously with Brodipim 1 g. The infusion system should be flushed before administration of metronidazole.

During prolonged (over 12 hours) surgical procedures, 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. The dose of cefepime should be adjusted in patients with impaired renal function (creatinine clearance less than 30 mL/min). The initial dose should be the same as for patients with normal renal function. Recommended maintenance doses of cefepime are shown in Table 4.

Recommended doses of Brodipim for adults

Table 4

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) = -------------------------------------------- ;

After preparation, the solution should be used immediately after dilution or stored for no more than 24 hours at a temperature of up to 25 °C, or for 7 days at a temperature of 2 to 8 °C.

As with other parenteral medicinal products, prepared 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 to determine susceptibility to cefepime. However, cefepime may be used as monotherapy prior to 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.

To be used in children aged 1 month and older.

Overdose.

Symptoms. In cases of significant overdose, particularly in patients with impaired renal function, adverse reactions may intensify. Symptoms of overdose include encephalopathy accompanied by hallucinations, disturbances of 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.

Adverse Reactions

Cefepime is generally well tolerated; however, the following adverse reactions may occur:

Immune system disorders: hypersensitivity reactions, rash, pruritus, fever, pyrexia, anaphylaxis, urticaria.

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

Cardiovascular disorders: chest pain, vasodilation, tachycardia.

Respiratory disorders: cough, throat pain, dyspnea.

Nervous system disorders: headache, dizziness, insomnia, paresthesia, restlessness, confusion, seizures, epileptiform seizures.

Reproductive system disorders: genital pruritus, vaginal candidiasis.

Urinary system disorders: vaginitis, genital pruritus.

Other: asthenia, sweating, pyrexia, erythema, peripheral edema, back pain.

Local reactions at the site of administration:

Intravenous administration: phlebitis and inflammation;

Intramuscular administration: injection site pain, inflammation.

Post-marketing studies:

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

Hepatitis and cholestatic jaundice occur very rarely.

Encephalopathy, myoclonia, and/or renal dysfunction have been reported in patients with renal impairment who received incorrect doses of cefepime.

Laboratory test abnormalities may rarely occur. Adverse effects were mostly transient. Elevated levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin, anemia, eosinophilia, thrombocytopenia, prolonged prothrombin time or partial thromboplastin time (PTT), and positive Coombs test without hemolysis have been observed. Transient increases in blood urea nitrogen and/or serum creatinine, as well as transient thrombocytopenia, were reported in less than 0.5% of patients. Leukopenia and neutropenia have also been reported.

Local reactions following intravenous infusion (phlebitis and inflammation) and intramuscular injection occur rarely.

Other adverse reactions typical for cephalosporin antibiotics are possible: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhage, hepatic dysfunction, cholestasis, pancytopenia.

Shelf life.

2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Reconstituted solutions are stable for 24 hours at room temperature or for 7 days if stored 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 section "Administration and Dosage."

Packaging.

1000 mg of powder for solution for injection, 1 vial per cardboard box.

Prescription category.

Prescription only.

Manufacturer.

Zeiss Pharmaceuticals Pvt. Ltd.;
Swiss Parenterals Ltd.

Manufacturer's address and place of business.

Plot No. 72, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan, (H. P.), India;
Unit II, Plot No. 402, 412-414 Kerala Industrial Estate, GIDC, Near Bavla, Ahmedabad, Gujarat, 382220, India