Forgenpim-1000

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FORGENPIME – 1000 (FORGENPIME – 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 from white to light yellow in color.

Pharmacotherapeutic group.

Antibacterials for systemic use. Fourth-generation cephalosporins.

ATC code J01D E01.

Pharmacological Properties.

Pharmacodynamics.

Cefepime is a broad-spectrum, fourth-generation β-lactam cephalosporin antibiotic 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 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 for penicillin-binding protein PBP 3 significantly exceeds that of other parenteral cephalosporins. Moderate affinity of cefepime for PBP 1a and 1b also contributes to its level of bactericidal activity. The ratio of MBC (minimum bactericidal concentration) to MIC (minimum inhibitory concentration) 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-lactamase-producing strains); other staphylococcal strains (including S. hominis, S. saprophyticus), Streptococcus pyogenes (group A); Streptococcus agalactiae (group B); Streptococcus pneumoniae (including strains with intermediate penicillin resistance—MIC from 0.1 to 1 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 cefepime and most other cephalosporins);

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 presented 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 with intravenous doses up to 2 g administered every 8 hours over 9 days.

Cefepime is metabolized to N-methylpyrrolidine, which is rapidly converted to N-methylpyrrolidine oxide. Cefepime is primarily eliminated by 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, approximately 6.8% as N-methylpyrrolidine oxide, and approximately 2.5% as the 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 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. For patients with abnormal renal function, the dose should be individually adjusted.

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, the mean total clearance and 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. No drug accumulation was observed with a dosing regimen of 50 mg/kg every 12 hours, whereas plasma maximum concentration, area under the curve, and elimination half-life increased by approximately 15% at steady state when administered every 8 hours at 50 mg/kg. Cefepime exposure in children after intravenous administration of 50 mg/kg was similar to that in adults after intravenous administration of 2 g. At steady state, the mean peak plasma concentration of cefepime after intravenous administration 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%.

When identification of the causative pathogen and determination of its antibiotic susceptibility are not feasible or when there is insufficient time, cefepime may be used empirically due to its broad antibacterial spectrum. In patients at risk of mixed aerobic-anaerobic infections, treatment with cefepime in combination with an anti-anaerobic agent may be initiated prior to 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.

For empirical therapy in patients with febrile neutropenia.

For prophylaxis of postoperative complications in intra-abdominal surgery.

Children.

Pneumonia.

Urinary tract infections, including pyelonephritis.

Skin and soft tissue infections.

Sepsis.

For empirical therapy in patients with febrile neutropenia.

Bacterial meningitis.

Contraindications.

Hypersensitivity to cefepime or to L-arginine, as well as to cephalosporins, 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 after 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; lactated Ringer's injection with 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 the medicinal product "Forgenpim – 1000" with these agents is necessary, each antibiotic should be administered separately.

Effect on laboratory test results

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

Special precautions for use.

Monotherapy may be insufficient for patients at high risk of severe infections (e.g., patients with a history of bone marrow transplantation and impaired bone marrow function due to severe progressive neutropenia associated with malignant hematologic disorders); therefore, combination antimicrobial therapy is indicated.

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

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

Cases of pseudomembranous colitis have been reported with the use of nearly all broad-spectrum antibiotics. Therefore, the possibility of this condition should be considered in patients who develop diarrhea during treatment. Evidence suggests 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 cases of pseudomembranous colitis may resolve after discontinuation of the drug. In cases of moderate or severe colitis, consideration should be given to administration of fluids and electrolytes, protein supplementation, and use of an antibacterial agent effective against Clostridium difficile.

Dosage adjustment of cefepime is required in patients with impaired renal function (creatinine clearance ≤ 60 mL/min) to compensate for reduced renal elimination. Because serum antibiotic concentrations may persist longer when cefepime is administered at usual doses in patients with renal impairment or other conditions affecting renal function, the maintenance dose of cefepime should be reduced in such patients. The degree of renal impairment, severity of infection, and microbial susceptibility to the antibiotic should be considered when determining the next dose of cefepime. During post-marketing surveillance of cefepime products, severe, life-threatening, or fatal adverse reactions have been reported, including 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. However, such reactions have occasionally occurred in patients receiving doses adjusted according to renal function. Symptoms of neurotoxicity were mostly reversible and resolved after discontinuation of cefepime and/or hemodialysis.

Warnings

It is unlikely that administration of cefepime in the absence of confirmed or strongly suspected bacterial infection, or for prophylactic use, will be beneficial; moreover, such use increases the risk of emergence of bacteria resistant to this drug. Prolonged use of cefepime (as with other antibiotics) may lead to superinfection. Repeated patient evaluation is necessary. If superinfection develops, appropriate measures should be taken.

Many cephalosporins, including cefepime, are associated with reduced prothrombin activity. High-risk patients include those with impaired hepatic or renal function, those 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.

A positive direct Coombs' test may occur during cefepime therapy. When performing hematological or transfusion procedures, including blood group determination by cross-matching, antiglobulin testing, or Coombs' testing in newborns whose mothers received cephalosporin antibiotics before delivery, it should be considered that a positive Coombs' test may result from drug administration.

L-arginine has been shown to alter glucose metabolism and simultaneously increase serum potassium levels when administered at doses 33 times higher than the maximum recommended dose of cefepime. Effects at lower doses are not yet known.

Use during pregnancy or breastfeeding.

The drug may be prescribed during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

Cefepime is excreted in low concentrations in breast milk; therefore, breastfeeding should be discontinued during treatment.

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 involving the nervous system may occur during treatment.

Method of Administration and Dosage.

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.

However, dosage and route of administration may vary depending on the susceptibility of the causative microorganisms, the severity of the infection, and the patient's renal function. Dosage recommendations for the medicinal product in 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, 60 minutes before the start of surgery in adults. After completion of the operation, additionally administer 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 (over 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, dose adjustment is required 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 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 hemodialysis, approximately 68% of the drug dose is removed from the body over 3 hours. A supplemental dose equal to the initial dose must be administered after each dialysis session. For continuous ambulatory peritoneal dialysis (CAPD), the drug may 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 medicinal product 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 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.

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 injections 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 infusion system or directly into a compatible infusion solution (administered over 30 minutes).

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

Intramuscular administration. The medicinal product may be dissolved in water for injections, 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 may be stored for up to 24 hours at a temperature not exceeding 25°C or 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 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 (including Bacteroides fragilis) infection, treatment may be initiated in combination with an agent active against anaerobes, pending identification of the causative organism.

Children.

The medicinal product can 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, disturbances of consciousness, stupor, coma, myoclonus, epileptiform seizures, and neuromuscular excitability.

Treatment. Administration of the drug should be discontinued and symptomatic therapy initiated. Hemodialysis accelerates the elimination of cefepime from the body; peritoneal dialysis is poorly effective. Severe immediate-type allergic reactions require administration of epinephrine and other forms of intensive therapy.

Adverse reactions.

Immune system disorders: hypersensitivity reactions, including anaphylaxis, anaphylactic shock, angioneurotic edema.

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

Cardiovascular system disorders: tachycardia, vasodilation, chest pain.

Gastrointestinal disorders: nausea, vomiting, dyspepsia, oral candidiasis, taste alteration, 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 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 for cephalosporin antibiotics: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhages, hepatic dysfunction, 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 medicinal product should not be mixed in the same container with other drugs (such as metronidazole, vancomycin, gentamicin, tobramycin or netilmicin solutions), except for the diluents specified in the section "Method of administration and dosage."

Packaging.

1 vial with the drug in a cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

Sens Laboratory Pvt. Ltd.

Manufacturer's address and location of business activity.

VI/51B, P.O. Box No. 2, Kozhuvanal, Pala, Kottayam – 686 573, Kerala, India.