Sanpim-1000

INSTRUCTION for medical use of the medicinal product SANPIME-1000 (SANPIME-1000)

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 of white to light yellow color.

Pharmacotherapeutic group.

Antibacterial agents for systemic use. Fourth-generation cephalosporins.

ATC code J01D E01.

Pharmacological Properties

Pharmacodynamics

Cefepime is a broad-spectrum β-lactam cephalosporin antibiotic of the 4th generation intended for parenteral administration. It exerts a bactericidal effect. It is active against Gram-positive and Gram-negative bacteria, including most strains resistant to aminoglycosides or 3rd-generation cephalosporin antibiotics such as ceftazidime. Cefepime is highly stable against the action 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 level of 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 the synthesis of bacterial cell wall enzymes. The drug has low affinity for chromosomally encoded β-lactamases.

Cefepime is active against the following microorganisms:

Gram-positive aerobes: Staphylococcus aureus (including β-lactamase-producing strains) and Staphylococcus epidermidis (including β-lactam ̄ase-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 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, 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 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 (mcg/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 is independent of dose within the range of 250 mg to 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 to N-methylpyrrolidine oxide. Cefepime is primarily eliminated via glomerular filtration (total cefepime clearance is approximately 120 mL/min, with mean hepatic 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 does not depend on 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 is observed 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 should be individualized for patients with abnormal renal function.

The pharmacokinetics of cefepime are not altered in patients with hepatic impairment or cystic fibrosis. 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 doses administered every 8 or every 12 hours. After a single intravenous injection, the mean total clearance from the body and the steady-state volume of distribution were 3.3 (1.0) mL/min/kg and 0.3 (0.1) L/kg, respectively. Renal excretion of unchanged cefepime was 60.4 (30.4)% of the administered dose, and mean renal clearance was 2 (1.1) mL/min/kg. Patient age and sex did not significantly affect total drug clearance or volume of distribution when corrected for body weight. When cefepime was administered at a dose of 50 mg/kg every 12 hours, no drug accumulation was observed, whereas with dosing at 50 mg/kg every 8 hours, plasma maximum 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 in adults receiving a 2 g intravenous dose. After intravenous administration, the mean peak plasma concentration of cefepime at steady state was 68 µg/mL, reached within 0.75 hours. Eight hours after intramuscular injection, the mean plasma concentration of cefepime was 6 µg/mL. The absolute bioavailability of cefepime after intramuscular injection averaged 82%.

Due to the inability to identify the causative pathogen and determine its antibiotic susceptibility, 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 infection, treatment with cefepime in combination with an anti-anaerobic agent may be initiated before pathogen identification.

Clinical characteristics.

Indications.

Adults.

Infections caused by microorganisms sensitive to the drug:

• respiratory tract, including pneumonia, bronchitis;
• skin and subcutaneous tissue;
• intra-abdominal infections, including peritonitis and biliary tract infections;
• urinary tract infections, including pyelonephritis;
• gynecological infections;
• sepsis.

Empirical therapy in patients with febrile neutropenia.

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 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 types of interactions.

When using 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 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 solution; 5% and 10% glucose injection solutions; 6 M sodium lactate injection solution; 5% glucose and 0.9% sodium chloride injection solution; Ringer's lactate solution and 5% glucose injection solution.

To avoid potential drug interactions with other agents, solutions of the drug Sanpim-1000 (like most other β-lactam antibiotics) should not be administered simultaneously with metronidazole, vancomycin, gentamicin, tobramycin sulfate, or netilmicin sulfate solutions. If co-administration of Sanpim-1000 with any of these agents is necessary, each antibiotic should be administered separately.

Effect on laboratory test results.

Administration of cefepime 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 use.

In patients at high risk of severe infections (e.g., patients with a history of bone marrow transplantation associated with reduced marrow activity due to severe progressive malignant hematologic disorders with severe neutropenia), 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 form of allergy, particularly drug allergies. If an allergic reaction occurs, administration of the drug must be discontinued. Severe immediate-type hypersensitivity reactions may require administration of epinephrine and other therapeutic interventions.

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

Cases of pseudomembranous colitis have been reported during treatment with nearly all broad-spectrum antibiotics. Therefore, it is important to consider the possibility of this condition developing in cases of diarrhea occurring during therapy. 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 cases of moderate or severe colitis, consideration should be given to the need for fluid and electrolyte replacement, protein supplementation, and administration 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. Since prolonged serum concentrations of the antibiotic may occur when cefepime is administered at usual doses in patients with renal impairment or other conditions that may worsen 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 adverse events, including life-threatening or fatal cases, 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 doses of cefepime exceeding the recommended doses. 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.

Warnings.

It is unlikely that administration of cefepime in the absence of proven or suspected bacterial infection, or for prophylactic use, will be beneficial; moreover, 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. The patient's condition should be re-evaluated periodically. 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.

During cefepime therapy, positive results in the direct Coombs test may be obtained. When performing hematological or transfusion procedures, including blood group cross-matching involving 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 result from 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 remain unknown.

Use during pregnancy or breastfeeding.

The drug 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 method of administration.

The usual dose for adults is 1000 mg, administered intravenously or intramuscularly every 12 hours. The usual duration of treatment is 7–10 days; severe infections may require longer treatment.

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

Table 2

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

During prolonged surgical procedures (exceeding 12 hours), a repeat dose of cefepime equal to the initial dose should be administered 12 hours after the first dose, followed by administration of metronidazole.

Renal function impairment. Cefepime is eliminated by the kidneys via glomerular filtration; therefore, dosage adjustment is required 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 given 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 removed 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 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 febrile neutropenia and 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 doses as recommended for adults.

In children 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)

The drug can be administered via deep intramuscular injection (0.5 g and 1 g), slow intravenous injection, or infusion (over 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 given directly into the vein by slow (3–5 minutes) injection via 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 solution (with or without 5% dextrose); 5% and 10% dextrose injection solutions; 1/6 M sodium lactate injection solution; Ringer’s lactate solution (with or without 5% dextrose).

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

The prepared solution may be stored for up to 24 hours at temperatures not exceeding 30°C or for up to 7 days at 2–8°C.

Table 4

As with other parenterally administered medicinal products, prepared solutions of the drug should be inspected visually for 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 pathogen identification.

Children.

The drug may be administered to 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, 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. Immediate-type severe allergic reactions require administration of adrenaline and other forms of intensive therapy.

Side effects

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 mucosal 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), myoclonus, confusion.

Hepatobiliary disorders: hepatitis, cholestatic jaundice.

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

Other adverse 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 at injection site, 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 of cephalosporin antibiotics: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhage, liver function disorders, cholestasis, pancytopenia.

Shelf life.

3 years.

Storage conditions.

Store at a temperature not exceeding 30 °C in the original packaging.

Keep out of reach of children.

Incompatibility.

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

Packaging.

1 vial per cardboard package.

Prescription status.

Prescription only.

Manufacturer.

Sens Laboratory Pvt. Ltd.

Manufacturer's address and place of business.

VI/51B, Post Office No. 2, Kozhuvanal, Pala, Kottayam – 686 573, Kerala, India.