Blipim

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

Composition:

Active ingredient: 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 from white to light yellow in color.

Pharmacotherapeutic group.

Antibacterials for systemic use. Other beta-lactam antibiotics. Fourth-generation cephalosporins. Cefepime. ATC code J01D E01.

Pharmacological properties.

Pharmacodynamics.

Cefepime is a β-lactam cephalosporin antibiotic of the fourth generation with a broad spectrum of activity 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 such as ceftazidime. Cefepime is highly stable against the action of most β-lactamases and rapidly penetrates Gram-negative bacteria. The degree of cefepime binding to penicillin-binding proteins (PBPs) significantly exceeds the affinity of other parenteral cephalosporins. The 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 the synthesis of bacterial cell wall enzymes 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 (including β-lactamase-producing strains), 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 0.3 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 (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 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 administration.

Mean plasma concentrations of cefepime in healthy adult patients 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 achieved in urine, bile, peritoneal fluid, bronchial mucous secretions, sputum, prostate, appendix, and gallbladder.

The elimination half-life of cefepime is approximately 2 hours and is independent of dose within the range of 250 mg to 2 g. No drug accumulation was observed with intravenous doses up to 2 g administered every 8 hours for 9 days.

Cefepime is metabolized to N-methylpyrrolidine, which is rapidly converted into N-methylpyrrolidine oxide. Cefepime is primarily eliminated via glomerular filtration (total cefepime clearance is approximately 120 mL/min, with mean renal clearance of 110 mL/min). Approximately 80–85% 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. Plasma protein binding of cefepime is less than 19% and is independent of drug concentration in serum.

Dose adjustment is not required for patients aged 65 years and older with normal renal function.

In patients with renal impairment, the elimination half-life of cefepime is prolonged, and a linear relationship exists between total drug clearance and creatinine clearance. The elimination half-life in patients with severe renal impairment requiring hemodialysis is 13 hours, and 19 hours in those undergoing continuous ambulatory peritoneal dialysis. Dose adjustment for patients with abnormal renal function should be individualized.

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

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.

Prophylaxis 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.

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 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 following concomitant administration 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% dextrose injections; 6% sodium lactate injection; 5% dextrose and 0.9% sodium chloride injection; Ringer's lactate with 5% dextrose injection.

To avoid potential drug interactions, Blipim should not be administered simultaneously with metronidazole, vancomycin, gentamicin, tobramycin sulfate, or netilmicin sulfate solutions. If co-administration with these agents is necessary, each antibiotic should be administered separately.

Effect on laboratory test results.

Cefepime may lead to 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 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 form of allergy, especially drug allergies. If an allergic reaction occurs, the drug should be discontinued. Severe immediate-type hypersensitivity reactions may require epinephrine and other therapeutic interventions.

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 Blipim. Pseudomembranous colitis may range from mild diarrhea to fatal colitis. Mild cases of colitis were reversible and resolved after discontinuation of cefepime; moderate or severe cases may require specific treatment.

Cautious administration is recommended in patients with gastrointestinal disorders, particularly colitis.

A skin sensitivity test should be performed before administration.

During prolonged treatment, liver, kidney, and hematopoietic system function should be monitored regularly.

In patients with impaired renal function (creatinine clearance < 60 mL/min), the dose of cefepime should be adjusted to compensate for reduced renal elimination. Since prolonged antibiotic serum concentrations may occur at standard doses in patients with renal impairment or other conditions that may impair kidney 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 encephalopathies (confusion, including clouding of 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 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 after hemodialysis.

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

Antibacterial agents may alter the normal flora of the colon and may lead to overgrowth of Clostridium species. 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 taken. Mild pseudomembranous colitis may resolve after discontinuation of the drug. In cases of moderate to severe colitis, the use of fluids and electrolytes, protein supplementation, and administration of an antibacterial agent effective against Clostridium difficile should be considered.

Warnings.

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 emergence of 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 regularly. If superinfection develops, appropriate measures should be taken.

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.

Positive results in the direct Coombs' test may occur during cefepime therapy. When performing hematological or transfusion procedures, including blood group determination by cross-matching, when performing the antiglobulin test or during 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.

When using lidocaine as a solvent in pediatric patients, 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.

Use during pregnancy or breastfeeding.

The drug may be used only when the expected benefit to the mother outweighs the potential risk to the fetus.

Cefepime penetrates into breast milk in very low concentrations. Therefore, breastfeeding should be discontinued during treatment with this drug.

Ability to affect reaction speed when driving or operating machinery.

Since adverse reactions involving the central nervous system may occur during treatment, patients should refrain from driving 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 treatment.

However, the dosage and route of administration should be adjusted depending on the susceptibility of the causative microorganisms, the severity of the infection, and the patient's renal function. Dosage recommendations for cefepime in adults are provided in Table 2.

Table 2

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

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

Renal function impairment. The dose of the drug should be adjusted in patients with impaired renal function (creatinine clearance less than 30 mL/min). The initial dose should be the same as that for patients with normal renal function. Recommended maintenance doses of cefepime are shown in Table 3.

Recommended doses of cefepime for adults

Table 3

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 dose is eliminated from the body over 3 hours. After each dialysis session, a supplemental dose equal to the initial dose should be administered. Cefepime can be used in the initial normal recommended doses of 500 mg, 1 g, or 2 g, depending on the severity of infection, every 48 hours in patients undergoing continuous ambulatory peritoneal dialysis.

Cefepime should be administered to infants aged 1–2 months only if absolutely necessary. Children weighing less than 40 kg receiving cefepime should be closely monitored.

Dosage reduction or increased dosing intervals are recommended for pediatric patients with impaired renal function.

Calculation of creatinine clearance in children:

or

Children aged 1 to 2 months. Only under life-threatening indications: 30 mg/kg body weight every 12 or 8 hours.

Children aged 2 months and older. The maximum dose for children must not exceed the recommended adult dose. The usual recommended dose for children with body weight up to 40 kg, in cases of 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.

Administration of the drug. Cefepime can be administered intravenously or intramuscularly 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, Blipim should be dissolved in 5 ml or 10 ml of sterile water for injections, 5% glucose solution 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. Blipim 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 paraben or benzyl alcohol, or 0.5% or
1% lidocaine hydrochloride solution, at concentrations specified in Table 4 below.

When using lidocaine as a solvent, a skin test for tolerance should be performed prior to administration.

Table 4

After preparation, the solution should be used immediately after dilution or can be stored for no more than 24 hours at a temperature of up to 25°C and for 7 days at a temperature from 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 performed to identify the causative microorganism(s) and determine susceptibility to cefepime. However, cefepime may be used as monotherapy prior to identification of the causative microorganism due to its broad antibacterial spectrum of activity against both 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, 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 epinephrine and other forms of intensive therapy.

Adverse Reactions

Cefepime is generally well tolerated, with adverse effects occurring rarely, at a frequency of 0.1–1%.

Immune system disorders: Hypersensitivity reactions, including anaphylaxis, anaphylactic shock, and angioedema.

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

Cardiovascular system disorders: Tachycardia, vasodilation.

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

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

Hepatobiliary disorders: Hepatitis, cholestatic jaundice.

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

Other reactions: 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 (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin; anemia, eosinophilia, prolonged prothrombin time or partial thromboplastin time, and a 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 of cephalosporin antibiotics: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhage, liver function disorders, cholestasis, pancytopenia.

Reporting of suspected adverse reactions

Reporting of adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life

3 years.

Storage conditions

Store 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 "Administration and dosage".

Packaging

1000 mg of powder for injection solution in vials, pack of 1 or 10 vials in cardboard boxes.

Prescription status

Prescription only.

Manufacturer

Zeiss Pharmaceuticals Pvt. Ltd.

Manufacturer's address

Plot No. 72, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan, (H. P.), India.

Marketing Authorization Holder

AAR PHARMA FZ-LLC.

Address of Marketing Authorization Holder

Premises 702, 7th Floor, Building: DSC Tower, Post Box – 478837, Dubai, United Arab Emirates.