Zinnat

I N S T R U C T I O N for medical use of the medicinal product Zinnat® (Zinnat®)

Composition:

Active substance: cefuroxime;

5 ml of ready-made suspension in a vial contains cefuroxime (in the form of cefuroxime axetil) 125 mg or 250 mg;

Excipients: povidone K30, stearic acid, sucrose, fruit flavoring, aspartame (E 951), xanthan gum, acesulfame potassium.

Pharmaceutical form. Granules for preparing a suspension.

Main physico-chemical characteristics: white or almost white free-flowing granules.

Pharmacotherapeutic group. Antimicrobial agents for systemic use. Beta-lactam antibiotics. ATC code J01D C02.

Pharmacological properties.

Pharmacodynamics.

Cefuroxime axetil is an oral form of the bactericidal cephalosporin antibiotic cefuroxime, which is resistant to the action of most beta-lactamases and exhibits activity against a broad spectrum of Gram-positive and Gram-negative microorganisms.

The bactericidal effect of cefuroxime results from inhibition of microbial cell wall synthesis.

Acquired resistance to the antibiotic varies among different regions and may change over time, with significant differences possible between individual strains. It is advisable, whenever possible, to refer to local data on antibiotic susceptibility, especially when treating severe infections.

Cefuroxime generally demonstrates in vitro activity against the following microorganisms:

*All methicillin-resistant S. aureus are resistant to cefuroxime.

Pharmacokinetics.

After oral administration, cefuroxime axetil is absorbed in the intestine, hydrolyzed in the mucosa, and enters the bloodstream as cefuroxime.

The absorption of Zinnat suspension is enhanced when taken simultaneously with food. The absorption level of cefuroxime suspension is lower than that of tablets, resulting in lower plasma drug levels and reduced systemic bioavailability. The maximum serum concentration of cefuroxime is reached approximately 2–3 hours after administration. The elimination half-life of the drug is about 1–1.5 hours. Protein binding ranges from 33% to 55%, depending on the method of determination. Cefuroxime is excreted unchanged by the kidneys via tubular secretion and glomerular filtration.

Concomitant administration of probenecid increases the area under the serum concentration-time curve by 50%.

Serum levels of cefuroxime are reduced by dialysis.

Clinical characteristics.

Indications.

Zinnat is indicated for the treatment of the following infections in adults and children aged 3 months and older:

• Acute streptococcal tonsillitis and pharyngitis.
• Acute bacterial sinusitis.
• Acute otitis media.
• Exacerbations of chronic bronchitis caused by pathogens sensitive to cefuroxime axetil.
• Cystitis.
• Pyelonephritis.
• Uncomplicated skin and soft tissue infections.
• Early manifestations of Lyme disease.

Contraindications.

Hypersensitivity to cephalosporin antibiotics, cefuroxime, or any component of the drug. History of severe hypersensitivity reactions (e.g., anaphylactic reactions) to any other type of beta-lactam antibiotics (penicillins, monobactams, and carbapenems).

Interaction with other medicinal products and other forms of interaction.

Agents that reduce gastric acidity may decrease the bioavailability of Zinnat and may counteract the food-induced acceleration of drug absorption.

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

Since pseudonegative results may occur with the ferricyanide test, glucose levels in blood and plasma of patients receiving cefuroxime axetil should be determined using glucose oxidase or hexokinase methods. Cefuroxime does not interfere with the alkaline picrate assay for creatinine determination.

Concomitant administration with probenecid leads to a significant reduction in maximum concentration, area under the serum concentration–time curve, and half-life of cefuroxime. Therefore, concomitant use with probenecid is not recommended.

Concomitant use with oral anticoagulants may lead to an increased INR (International Normalized Ratio).

Serum cefuroxime levels are reduced by dialysis.

Positive Coombs' test results have been reported during treatment with cephalosporins. This phenomenon may affect blood compatibility cross-matching tests.

Special precautions for use.

Hypersensitivity reactions

Particular caution is required in patients with a history of allergic reactions to penicillins or other beta-lactam antibiotics due to the risk of cross-sensitivity. As with all beta-lactam antimicrobial agents, serious and sometimes fatal hypersensitivity reactions have been reported. In the event of severe hypersensitivity reactions, treatment with cefuroxime should be discontinued immediately and appropriate emergency medical care should be provided.

Prior to initiating therapy, it is necessary to determine whether the patient has previously experienced severe hypersensitivity reactions to cefuroxime, other cephalosporins, or other types of beta-lactam agents. Cefuroxime should be administered with caution to patients with a history of mild hypersensitivity reactions to other beta-lactam medicinal products.

Particular caution is required in patients with a history of allergic reaction to penicillins or other beta-lactam antibiotics.

The use of cefuroxime axetil (as with other antibiotics) may lead to overgrowth of Candida. Prolonged use may also result in overgrowth of other resistant microorganisms (e.g., Enterococci, Clostridium difficile), which may require discontinuation of treatment.

Pseudomembranous colitis, ranging from mild to life-threatening, may develop during or after antibiotic therapy. Therefore, this should be considered if patients develop diarrhea during or after antibacterial treatment. If prolonged or pronounced diarrhea occurs, or if the patient experiences severe cramping abdominal pain, treatment should be discontinued immediately and the patient should be thoroughly evaluated.

The granules for oral suspension contain sucrose, which should be taken into account when prescribing the drug to patients with diabetes mellitus. The granules for oral suspension 125 mg/5 ml contain 3 g of sucrose per 5 ml dose. The granules for oral suspension 250 mg/5 ml contain 2.3 g of suc sugar per 5 ml dose.

Jarisch–Herxheimer reaction has been observed during treatment with Zinnat for Lyme disease, which occurs directly as a result of the bactericidal effect of Zinnat on the causative organism of Lyme disease, the spirochete Borrelia burgdorferi. Patients should be informed that this is a common phenomenon during antibiotic treatment of Lyme disease and does not require specific treatment.

The suspension contains aspartame, a source of phenylalanine, and therefore should not be used in patients with phenylketonuria.

When performing sequential therapy, the timing of switching from parenteral to oral treatment depends on the severity of infection, the patient's clinical condition, and the susceptibility of the causative microorganism. If there is no clinical improvement within 72 hours, parenteral therapy should be continued. Prior to initiating sequential therapy, the relevant instructions for medical use of sodium cefuroxime should be consulted.

Use during pregnancy or breastfeeding.

Pregnancy

There are limited data on the use of cefuroxime in pregnant women. Animal studies have not shown any adverse effects of cefuroxime axetil on pregnancy, embryonal or fetal development, parturition, or postnatal development. Zinnat should be prescribed to pregnant women only if the benefit of treatment outweighs the potential risks.

Breastfeeding

Cefuroxime passes into breast milk in small amounts. Adverse reactions are not expected when therapeutic doses are used; however, the risk of developing diarrhea or fungal infection of mucous membranes cannot be excluded. Therefore, breastfeeding may need to be discontinued due to these reactions. The possible sensitizing effect of the drug should also be considered. Cefuroxime should be administered during breastfeeding only after a physician has evaluated the benefit-risk ratio of its use.

Fertility

There are no data on the effect of cefuroxime axetil on fertility in humans. Reproductive function studies in animals have not shown any effect of this medicinal product on fertility.

Ability to affect reaction speed when driving or operating machinery.

Since the drug may cause dizziness, patients should be warned to exercise caution when driving or operating machinery.

Method of administration and dosage.

Sensitivity to antibiotics varies depending on the region and may change over time. When necessary, local antibiotic sensitivity data should be consulted.

The usual duration of treatment is 7 days (can range from 5 to 10 days).

To ensure better absorption, the suspension formulation of the drug should be taken during meals.

Dosage of the drug for adults and children depending on the infection is provided in Tables 1 and 2.

Adults and children (≥40 kg) Table 1

Children (< 40 kg) Table 2

For children aged 3 months, whose body weight is less than 40 kg, the dosage regimen is adjusted according to body weight or the child's age. For children aged 3 months to 18 years, the recommended dose is 10 mg/kg body weight twice daily for most infections (maximum daily dose 250 mg). For otitis media or more severe infections, the recommended dose is 15 mg/kg body weight twice daily (maximum daily dose 500 mg).

For convenience in administering the multidose suspension 125 mg/5 mL or 250 mg/5 mL, two tables (3, 4) are provided below, allowing simplified dose determination (e.g., using a 5 mL measuring spoon with an additional 2.5 mL mark) according to age and dosage form.

Table 3

10 mg/kg (twice daily) for most infections

Table 4

15 mg/kg (twice daily) for the treatment of moderate otitis and severe infections

Cefuroxime is also available as a sodium salt for parenteral administration ("Zinacef"). This allows for the sequential use of different forms of the same antibiotic when it is clinically appropriate to switch from parenteral to oral therapy.

The duration of both parenteral and oral treatment is determined according to the severity of infection and the patient's condition.

Patients with renal impairment

Cefuroxime is primarily eliminated via the kidneys. Patients with significantly impaired renal function should receive reduced doses of cefuroxime to compensate for its slower excretion (see Table 5).

Table 5

Patients with hepatic impairment

There are no data on the use of this medicinal product in patients with impaired liver function. Cefuroxime is eliminated mainly by the kidneys, therefore, existing liver function disorders are not expected to affect the pharmacokinetics of cefuroxime.

Instructions for dissolving granules in the vial:

Immediately after reconstitution, the suspension vial must be placed in the refrigerator for storage at 2–8 °C (do not freeze) and left for at least 1 hour before administration of the first dose. The reconstituted suspension may be stored for up to 10 days provided it is kept refrigerated at 2–8 °C.

The vial should always be shaken well before use. Use the provided measuring spoon to administer each dose.

If desired, the reconstituted suspension in the vial may be further diluted with cold fruit juice or milk immediately before administration and taken immediately after dilution.

Children.

There is no experience with the use of Zinnat for the treatment of children under 3 months of age.

Overdose.

In cases of cephalosporin overdose, central nervous system irritation and neurological complications may occur, including encephalopathy, seizures, and coma. Symptoms of overdose may arise if the drug dose has not been appropriately adjusted in patients with impaired renal function (see sections "Posology and method of administration" and "Special warnings and precautions for use").

Serum cefuroxime levels can be reduced by hemodialysis and peritoneal dialysis.

Adverse Reactions

Adverse reactions associated with the use of cefuroxime axetil are generally mild and mainly reversible.

The frequency categories of the adverse reactions listed below are estimates, as for most events (e.g., from placebo-controlled studies) adequate data for calculating exact frequencies are lacking. Moreover, the frequency of adverse reactions associated with cefuroxime axetil may vary depending on the indication for use.

Frequencies from very common to rare were derived from large clinical trials. The frequencies of all other adverse reactions (i.e., those occurring at a rate < 1/10,000) were primarily determined from post-marketing data. The resulting frequency is more indicative of reporting rates than of true incidence. Placebo-controlled trial data are unavailable. The frequency category calculated from clinical trial results is based on data related to the medicinal product (as assessed by the investigator physician).

The adverse reactions reported below are classified by system organ class and frequency of occurrence. Frequency categories: very common (≥ 1 in 10), common (≥ 1 in 100 to < 1 in 10), uncommon (≥ 1 in 1,000 to < 1 in 100), rare (≥ 1 in 10,000 to < 1 in 1,000), very rare (< 1 in 10,000), and not known (cannot be estimated from available data).

Infections and infestations

Common: overgrowth of Candida.

Not known: overgrowth of Clostridium difficile.

Blood and lymphatic system disorders

Common: eosinophilia.

Uncommon: positive Coombs test, thrombocytopenia, leucopenia (sometimes profound).

Very rare: haemolytic anaemia.

Cephalosporins as a class have the property of adsorbing to the surface of red blood cell membranes and interacting with antibodies, which may lead to a positive Coombs test (interfering with blood compatibility testing) and, very rarely, to haemolytic anaemia.

Immune system disorders

Hypersensitivity reactions, including:

Uncommon: skin rash.

Rare: urticaria, pruritus.

Very rare: drug fever, serum sickness, anaphylaxis.

Not known: Jarisch–Herxheimer reaction.

Nervous system disorders

Common: headache, dizziness.

Gastrointestinal disorders

Common: gastrointestinal disturbances including diarrhoea, nausea, abdominal pain.

Uncommon: vomiting.

Rare: pseudomembranous colitis (see section "Special precautions for use").

Hepatobiliary disorders

Common: transient elevations in liver enzymes (ALT, AST, LDH), which are usually reversible.

Very rare: jaundice (mainly cholestatic), hepatitis.

Skin and subcutaneous tissue disorders

Very rare: erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis (exanthematous necrolysis) (see "Immune system disorders").

Not known: angioneurotic oedema.

Children

The safety profile of cefuroxime in children corresponds to that observed in adult patients.

Shelf life. 2 years.

After reconstitution, the shelf life of the suspension in the bottle is up to 10 days when stored in a refrigerator at 2–8 °C.

Storage conditions.

Store below 30 °C. After reconstitution, store the suspension in a refrigerator at 2–8 °C. Keep out of the reach and sight of children.

Packaging.

Granules for the preparation of 100 ml of suspension in a dark glass bottle with a cap and protective membrane, with a plastic measuring cap on the lid. The bottle, together with the measuring cap and measuring spoon, is contained in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Glaxo Operations UK Limited (United Kingdom)

Manufacturer's address and site of operations.

Glaxo Operations UK Limited, Harmire Road, Barnard Castle, Durham, DL12 8DT, United Kingdom.