Skyphim

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

Composition:

Active substance: cefepime;

1 vial contains cefepime hydrochloride equivalent to cefepime 1000 mg;

Excipient: L-arginine.

Medicinal form. Powder for solution for injection.

Main physicochemical properties: powder from 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 fourth generation 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 cephalosporins 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 is significantly higher than that of other parenteral cephalosporins. Moderate affinity of cefepime to PBPs 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 the synthesis of enzymes in the bacterial cell wall. The drug has low affinity for chromosomally mediated β-lactamases.

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 resistance to penicillin – 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 (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.

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 to 2 g. No drug accumulation was observed after intravenous administration of doses up to 2 g every 8 hours for 9 days.

Cefepime is metabolized to N-methylpyrrolidine, which is rapidly converted to the N-methylpyrrolidine oxide. Cefepime is primarily eliminated by glomerular filtration (total cefepime clearance is approximately 120 mL/min, with average hepatic clearance of 110 mL/min). Approximately 80–85% of the dose is excreted in urine as unchanged cefepime, 1% as N-methylpyrrolidine, approximately 6.8% as N-methylpyrrolidine oxide, and approximately 2.5% as the cefepime epimer. Protein binding of cefepime to plasma proteins is less than 19% and does not depend on drug concentration in serum.

Dose adjustment is not required in 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 dysfunction requiring hemodialysis is 13 hours, and 19 hours in those undergoing continuous ambulatory peritoneal dialysis. Dose adjustment is necessary and should be individualized in 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 12 hours. After a single intravenous injection, 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. Excretion of unchanged cefepime in urine was 60.4 (30.4)% of the administered dose, and average 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. No drug accumulation was observed with a dosing regimen of 50 mg/kg every 12 hours, whereas maximum plasma concentration, area under the curve, and elimination half-life increased by approximately 15% at steady state with the regimen of 50 mg/kg every 8 hours. Cefepime exposure in children after intravenous administration of 50 mg/kg is comparable to that in adults after intravenous administration of 2 g. After intravenous administration, the average steady-state maximum plasma concentration of cefepime was 68 mcg/mL, reached within 0.75 hours. Eight hours after intramuscular injection, the average 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 antibiotic susceptibility, or due to lack of time, cefepime may be used as empirical therapy because of its broad-spectrum 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 infections, including pneumonia, bronchitis;
• skin and soft tissue infections;
• 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 soft tissue infections;
• sepsis;
• empirical therapy in patients with febrile neutropenia;
• bacterial meningitis.

Contraindications.

Hypersensitivity 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 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 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 solution and 5% glucose injection.

To avoid potential drug interactions with other agents, solutions of Cefepime (as with 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 Skyepim with these agents is necessary, 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 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 caused by malignant hemolytic 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 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, administration of the drug must be discontinued. Severe immediate-type hypersensitivity reactions may require treatment with adrenaline (epinephrine) and other therapeutic measures.

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

Cases of pseudomembranous colitis have been reported with nearly all broad-spectrum antibiotics. Therefore, it is important to consider the possibility of this condition in any patient who develops diarrhea during treatment with this drug. Evidence suggests that the toxin produced by Clostridium difficile is the primary cause of antibiotic-associated colitis. Once pseudomembranous colitis is confirmed, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis may resolve after discontinuation of the drug. In moderate or severe cases, consideration should be given to 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 slower renal elimination. Since prolonged serum concentrations of the antibiotic may occur when cefepime is administered at standard doses in patients with renal impairment or other conditions that may affect kidney 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 products, serious, life-threatening, or fatal adverse reactions have been reported, including encephalopathy (disturbances of consciousness, including confusion, hallucinations, stupor, and coma), myoclonus, and seizures. Most cases occurred in patients with impaired renal function who received cefepime doses exceeding the recommended levels. 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 its 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 superinfection. The patient's condition should be re-evaluated regularly. If superinfection develops, appropriate measures should be taken.

Many cephalosporins, including cefepime, are associated with reduced prothrombin activity. High-risk patients include those with impaired liver or kidney function, patients with poor nutrition, 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, such as blood grouping by the cross-matching method involving the antiglobulin test, or when performing the Coombs' test in newborns whose mothers received cephalosporin antibiotics before delivery, it should be noted that a positive Coombs' test may be due to the drug administration.

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

Use during pregnancy or breastfeeding.

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 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 when driving or operating machinery has not been studied; however, it should be noted that adverse reactions affecting the nervous system may occur during treatment.

Method of administration and dosage.

The usual dosage 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.

However, dosage and route of administration vary depending on the sensitivity of the causative microorganisms, 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. Administer 2 g of the drug intravenously over 30 minutes to adults 60 minutes before the start of surgery. After completion of the surgery, administer an additional 500 mg of metronidazole 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 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 must be adjusted in patients with impaired renal function (creatinine clearance less than 30 mL/min) (see Table 3).

Recommended doses of cefepime for adults

Table 3

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

If only 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) = above value × 0.85.

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

Children aged 1 to 2 months. The drug should be prescribed 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 cases of 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 (for patients with febrile neutropenia and bacterial meningitis – every 8 hours). 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.

For children with impaired renal function, dose reduction or increased dosing interval is 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 by deep intramuscular injection (0.5 g and 1 g), slow intravenous injection, or infusion (from 3–5 minutes 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 (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 can be dissolved in water for injection, 0.9% sodium chloride injection, 5% dextrose injection, 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 can be stored for up to 24 hours at temperatures not exceeding 30°C or up to 7 days at 2–8°C.

Table 4

As with other parenterally administered medicinal products, the prepared solution 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, 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 infection (including Bacteroides fragilis), treatment may be initiated in combination with an agent active against anaerobes, prior to identification of the causative organism.

Children.

The drug may be administered to children aged 1 month and older.

Overdose.

Symptoms. In cases of significant overdose, particularly in patients with impaired renal function, adverse effects are intensified. 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, and angioneurotic edema.

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

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 abnormalities: increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), 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 temperatures 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 carton.

Prescription status.

Prescription only.

Manufacturer.

Sens Laboratory Pvt. Ltd.

Manufacturer's address and site of operations.

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