Yokel

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT YOKEL (YOKEL)

Composition:

Active substance: cefuroxime;

1 vial contains: sodium cefuroxime equivalent to cefuroxime 750 mg.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white or almost white powder.

Pharmacotherapeutic group.

Antibacterial agents for systemic use. Second-generation cephalosporins. ATC code J01DC02.

Pharmacological properties.

Pharmacodynamics

Cefuroxime is a bactericidal cephalosporin antibiotic with high activity against a broad spectrum of Gram-positive and Gram-negative bacteria, including strains producing β-lactamases. Cefuroxime is resistant to the action of β-lactamases and therefore exhibits activity against many ampicillin- or amoxicillin-resistant strains. The primary mechanism of bactericidal action is inhibition of bacterial cell wall synthesis.

Cefuroxime is effective in vitro against the following microorganisms:

Gram-negative aerobes

Escherichia coli, Klebsiella spp., Proteus mirabilis, Proteus rettgeri, Providencia spp., Haemophilus influenzae (including ampicillin-resistant strains), Haemophilus parainfluenzae (including ampicillin-resistant strains), Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae (including penicillinase-producing strains), Neisseria meningitidis, Salmonella spp.;

Gram-positive aerobes

Staphylococcus aureus, Staphylococcus epidermidis (including penicillinase-producing strains, except methicillin-resistant strains), Streptococcus pyogenes (and other β-haemolytic streptococci), Streptococcus pneumoniae, Streptococcus group B (Streptococcus agalactiae), Streptococcus mitis (viridans group), Bordetella pertussis;

Anaerobes

Gram-positive and Gram-negative cocci (including Peptococcus and Peptostreptococcus species);

Gram-positive bacteria (including most Clostridium spp.), and Gram-negative bacteria (including Bacteroides spp. and Fusobacterium spp.), Propionibacterium spp.;

Other microorganisms

Borrelia burgdorferi.

Microorganisms not susceptible to cefuroxime

Clostridium difficile, Pseudomonas spp., Campylobacter spp., Acinetobacter calcoaceticus, Listeria monocytogenes, methicillin-resistant strains of Staphylococcus aureus, methicillin-resistant strains of Staphylococcus epidermidis, Legionella spp.

Some microorganism strains not susceptible to cefuroxime

Enterococcus (Streptococcus) faecalis, Morganella morganii, Proteus vulgaris, Enterobacter spp., Citrobacter spp., Serratia spp., Bacteroides fragilis.

In vitro studies have shown that when cefuroxime is combined with aminoglycoside antibiotics, an additive effect is observed, and in some cases, synergy occurs.

Pharmacokinetics

Maximum serum concentration of cefuroxime is achieved within 30–45 minutes after intramuscular administration. The elimination half-life of cefuroxime following intravenous or intramuscular administration is approximately 70 minutes. Concomitant administration of probenecid slows the excretion of cefuroxime and leads to increased serum concentrations.

Protein binding to serum proteins ranges from 33% to 50%.

Within 24 hours after administration, the drug is almost completely (85–90%) excreted unchanged in the urine, with the majority eliminated within the first 6 hours.

Cefuroxime is not metabolized and is excreted via glomerular filtration and tubular secretion.

Serum levels of cefuroxime are reduced by dialysis.

Cefuroxime concentrations exceeding the MIC (minimum inhibitory concentration) for most common pathogenic microorganisms are achieved in bone tissue, synovial fluid, and intraocular fluid. Cefuroxime crosses the blood-brain barrier during inflammation of the meninges.

Each 750 mg of cefuroxime (1 vial) contains 42 mg (1.8 mEq) of sodium.

Clinical characteristics.

Indications.

For the treatment of infections caused by microorganisms sensitive to cefuroxime, including before identification of the causative agent of the infectious disease:

• Community-acquired pneumonia;
• Exacerbation of chronic bronchitis;
• Complicated urinary tract infections, including pyelonephritis;
• Soft tissue infections: cellulitis, erysipelas, wound infections;
• Infections of the abdominal cavity (see section "Special precautions").

For prophylaxis of postoperative infections following gastrointestinal tract surgery, including the esophagus, orthopedic, gynecological surgeries (including cesarean section), and cardiovascular surgeries.

When treating and preventing infections caused by anaerobic microorganisms, cefuroxime should be used in combination with appropriate additional antibacterial agents.

Official recommendations regarding proper use of antibacterial agents should be taken into account.

Contraindications.

Hypersensitivity to cefuroxime, cephalosporin antibiotics, or history of severe hypersensitivity reactions (such as anaphylactic reactions) to other β-lactam antibiotics (penicillins, monobactams, carbapenems).

Interaction with other medicinal products and other types of interactions.

Like other antibiotics, Yokel may affect intestinal flora, leading to reduced reabsorption of estrogens and decreased effectiveness of combined oral contraceptives.

Cefuroxime is eliminated via glomerular filtration and tubular secretion. Concomitant use of probenecid is not recommended. Simultaneous administration of probenecid slows elimination of the antibiotic and increases its serum concentration.

Potentially nephrotoxic drugs and loop diuretics.

Cephalosporin antibiotics in high doses should be administered with caution in patients receiving treatment with potent diuretics (such as furosemide) or potentially nephrotoxic drugs (such as aminoglycoside antibiotics), since renal function impairment cannot be excluded with such drug combinations.

Other types of interactions.

Regarding determination of plasma glucose levels, see section "Special precautions."

Concomitant use with oral anticoagulants may lead to increased international normalized ratio (INR).

Special precautions for use.

Hypersensitivity reactions.

Severe and occasionally fatal hypersensitivity reactions have been reported with the use of β-lactam antibiotics. Hypersensitivity reactions progressing to Kounis syndrome (acute allergic coronary artery spasm, which may lead to myocardial infarction — see section "Adverse reactions") have been reported. In case of severe hypersensitivity reactions, treatment with cefuroxime should be discontinued immediately and appropriate emergency measures should be initiated.

Prior to initiating therapy, patients should be assessed for a history of severe hypersensitivity reactions to cefuroxime, other cephalosporins, or β-lactam agents. The drug should be administered with caution to patients with a history of hypersensitivity reactions to other β-lactam antibiotics.

Severe cutaneous adverse reactions.

Severe cutaneous adverse reactions, including Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), which may be life-threatening or fatal, have been reported in association with cefuroxime therapy (see section "Adverse reactions").

Patients should be informed of the signs and symptoms and closely monitored for skin reactions during treatment. If symptoms suggestive of these reactions occur, cefuroxime should be discontinued immediately and alternative therapy considered. Cefuroxime therapy must never be reinitiated in patients who have experienced a serious reaction such as SJS, TEN, or DRESS syndrome during treatment with cefuroxime.

Concomitant treatment with potent diuretics or aminoglycosides.

Cephalosporin antibiotics should be administered with caution in high doses to patients receiving concomitant potent diuretics, such as furosemide, or aminoglycosides, as cases of renal function impairment have been reported with such drug combinations. Renal function should be monitored in these patients, as well as in elderly patients and those with renal impairment (see section "Dosage and administration").

Overgrowth of resistant microorganisms.

Cefuroxime use may lead to overgrowth of Candida species. Prolonged use of cefuroxime may result in overgrowth of resistant microorganisms (such as Enterococci, Clostridium difficile), which may necessitate discontinuation of treatment (see section "Adverse reactions").

Cases of pseudomembranous colitis of varying severity, ranging from mild to life-threatening, have been reported during or after antibiotic therapy. Therefore, this diagnosis should be considered in patients who develop diarrhea during or after antibiotic use (see section "Adverse reactions"). Discontinuation of cefuroxime therapy and initiation of specific treatment against Clostridium difficile should be considered. Antiperistaltic agents are not recommended.

Intracameral administration and ocular adverse reactions.

Yokel is not intended for intracameral administration. Serious ocular adverse reactions have been reported following intracameral use of sodium cefuroxime intended for intravenous/intramuscular administration. These reactions include macular edema, retinal edema, retinal detachment, retinal toxicity, visual disturbances, decreased visual acuity, blurred vision, corneal opacification, and corneal edema.

Intra-abdominal infections.

Due to its spectrum of activity, cefuroxime is not suitable for the treatment of infections caused by gram-negative non-fermenting bacteria (see section "Pharmacodynamics").

Effect on diagnostic test results.

Positive Coombs test results have been reported during cefuroxime therapy. This phenomenon may affect cross-matching of blood compatibility (see section "Adverse reactions").

Minor interference with copper reduction methods (Benedict, Fehling, Clinitest) may occur. However, this should not lead to false-positive results as may be observed with some other cephalosporins.

False-negative results may occur with the ferricyanide test. Therefore, for determination of blood/plasma glucose levels in patients receiving sodium cefuroxime, glucose oxidase or hexokinase methods are recommended.

Excipients.

The medicinal product Yokel (750 mg vial) contains 42 mg of sodium per vial, corresponding to 2.1% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Use during pregnancy or breastfeeding

Pregnancy

Data on the use of cefuroxime in pregnant women are limited. Reproductive toxicity has not been observed in animal studies. Yokel should be used during pregnancy only if clearly needed and if the potential benefit justifies the potential risk to the fetus.

Cefuroxime crosses the placenta and reaches therapeutic levels in amniotic fluid and umbilical cord blood after intramuscular or intravenous administration to the mother.

Breastfeeding

Cefuroxime passes into breast milk in small amounts. Adverse reactions in the infant are not expected with therapeutic doses, but the risk of diarrhea or fungal mucosal infections cannot be excluded. Therefore, a decision should be made whether to discontinue breastfeeding or to discontinue/abstain from cefuroxime therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

There are no data on the effect of sodium cefuroxime on fertility in humans. No effects on fertility were observed in animal reproductive studies.

Ability to influence the speed of reactions when driving or operating machinery.

Due to the possibility of dizziness, the medicinal product may affect the ability to drive vehicles or operate machinery.

Dosage and administration.

Dosing

Table 1. Adults and children with body weight ≥ 40 kg

Table 2. Children with body weight < 40 kg

Renal dysfunction

Cefuroxime is primarily eliminated via the kidneys. Therefore, as with other similar antibiotics, patients with significantly impaired renal function should receive reduced doses of Yocel to compensate for the slower drug excretion.

Table 3. Recommended doses of the medicinal product Yocel in renal dysfunction

Hepatic impairment

Cefuroxime is primarily eliminated by the kidneys. No influence on the pharmacokinetics of cefuroxime has been observed in patients with hepatic dysfunction.

Method of administration

Yokel should be administered by intravenous injection over 3–5 minutes directly into the vein or via an infusion line, or by infusion over 30–60 minutes, or by deep intramuscular injection.

The site for intramuscular injection is the large gluteal muscle. No more than 750 mg should be injected at a single site; doses exceeding 1.5 g should be administered intravenously.

Dilution of the medicinal product prior to administration

* Reconstituted solution for addition to 50 or 100 ml of a compatible infusion fluid (see below for compatibility).

** The resulting volume of cefuroxime solution in the reconstituted medium increases due to the displacement factor of the active substance, forming the indicated concentrations.

Compatibility

1.5 g of Zavel (Yokel), dissolved in 15 ml of water for injections, can be used concomitantly with metronidazole injection (500 mg / 100 ml); both drugs retain their activity for 24 hours at temperatures not exceeding 25 °C.

1.5 g of Zavel (Yokel) is compatible with 1 g of azlocillin (in 15 ml of solvent) or with 5 g (in 50 ml of solvent) for 24 hours at 4 °C and for 6 hours at temperatures not exceeding 25 °C.

Zavel (Yokel) (5 mg/ml) can be stored for 24 hours at 25 °C in 5 % or 10 % xytilol injection solution.

Zavel (Yokel) is compatible with solutions containing up to 1 % lidocaine hydrochloride.

Zavel (Yokel) is compatible with most commonly used intravenous infusion solutions. It retains its properties for 24 hours at room temperature in the following solutions:

0.9 % sodium chloride injection solution;

5 % glucose injection solution;

0.18 % sodium chloride with 4 % glucose injection solution;

5 % glucose with 0.9 % sodium chloride injection solution;

5 % glucose with 0.45 % sodium chloride injection solution;

5 % glucose with 0.225 % sodium chloride injection solution;

10 % glucose injection solution;

10 % invert sugar solution in water for injections;

Ringer's solution;

Ringer's lactate solution;

1/6 M sodium lactate solution;

Hartmann's solution.

The stability of Zavel (Yokel) in 0.9 % sodium chloride injection solution with 5 % glucose is not altered in the presence of sodium hydrocortisone phosphate.

Zavel (Yokel) is also compatible for 24 hours at room temperature when diluted in infusion solutions containing:

heparin (10 or 50 units/ml) in 0.9 % sodium chloride injection solution;

potassium chloride solution (10 or 40 mEq/L) in 0.9 % sodium chloride injection solution.

Unused medicinal product or waste must be disposed of in accordance with local requirements.

Children.

Zavel (Yokel) is used in children from the first days of life. The safety profile of cefuroxime in children corresponds to that in adult patients.

Overdose.

Neurological complications, including encephalopathy, seizures, and coma, may occur in overdose. Symptoms of overdose may appear in patients with impaired renal function if the drug dose has not been appropriately adjusted (see sections "Special instructions" and "Dosage and administration").

Cefuroxime levels can be reduced by hemodialysis or peritoneal dialysis.

Adverse Reactions

The most commonly observed adverse reactions are neutropenia, eosinophilia, and transient elevations in liver enzymes or bilirubin, particularly in patients with pre-existing liver disease; however, there is no evidence of harmful effects on the liver or injection site reactions.

The frequency of the adverse reactions listed below is approximate, as there are insufficient data to determine exact frequencies for most of these reactions. In addition, the incidence of adverse reactions associated with cefuroxime varies depending on the indication.

Data on adverse effects were obtained from clinical trials and post-marketing experience.

The following classification is used to describe the frequency of adverse reactions: very common — ≥ 1/10; common — ≥ 1/100 to < 1/10; uncommon — ≥ 1/1,000 to < 1/100; rare — ≥ 1/10,000 to < 1/1,000; very rare — < 1/10,000; frequency not known (cannot be estimated from available data).

Infections and infestations: frequency not known — overgrowth of Candida or Clostridium difficile.

Cardiac disorders: frequency not known — Kounis syndrome.

Blood and lymphatic system disorders: common — neutropenia, eosinophilia, decreased hemoglobin levels; uncommon — leukopenia, positive Coombs test; frequency not known — thrombocytopenia, hemolytic anemia.

Immune system disorders: frequency not known — drug fever, interstitial nephritis, anaphylaxis, cutaneous vasculitis.

Gastrointestinal disorders: uncommon — gastrointestinal discomfort; frequency not known — pseudomembranous colitis (see section "Special precautions for use").

Hepatobiliary disorders: common — transient increase in liver enzymes; uncommon — transient increase in bilirubin levels.

Skin and subcutaneous tissue disorders: uncommon — skin rash, urticaria, pruritus; frequency not known — erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, angioneurotic edema, frequency not known — drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

Renal and urinary disorders: frequency not known — increased serum creatinine, blood urea nitrogen (BUN), and decreased creatinine clearance (see section "Special precautions for use").

General disorders and administration site conditions: common — injection site reactions, which may include pain and thrombophlebitis.

Description of selected adverse reactions

Cephalosporins may adsorb onto the surface of red blood cell membranes and interact with antibodies, potentially leading to a positive Coombs test (which may interfere with cross-matching blood) and, very rarely, hemolytic anemia.

Transient elevations in serum liver enzymes or bilirubin were reversible in nature.

The likelihood of pain at the intramuscular injection site is higher with higher doses. However, this is unlikely to necessitate discontinuation of treatment.

Reporting of adverse reactions

Reporting suspected adverse reactions after drug authorization is of great importance. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life

2 years

Storage conditions

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

Keep out of reach of children.

After reconstitution for intravenous or intramuscular injection, the solution may be stored for up to 24 hours in a refrigerator at 2–8 °C.

Incompatibilities

Yokel must not be mixed in the same syringe with aminoglycoside antibiotics.

The pH of a 2.74% sodium bicarbonate injection solution significantly affects the color of the solution; therefore, this solution is not recommended for dilution of Yokel. However, if necessary, when a patient is receiving intravenous sodium bicarbonate infusion, Yokel may be administered directly into the infusion line.

Packaging

750 mg powder for injection solution in a vial No. 1 in a cardboard box.

Prescription status Prescription only.

Manufacturer

BROS LTD, Greece / BROS LTD, Greece.

Manufacturer's address and place of business

Augis & Galinis 15, Nea Kifisia (Attiki) 14564, Greece / Augis & Galinis 15, Nea Kifisia (Attiki) 14564, Greece.