Axetin

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT AXCETIN® (AXETINE)

Composition:

Active substance: cefuroxime;

1 tablet contains cefuroxime (in the form of cefuroxime axetil) 250 mg or 500 mg;

Excipients: microcrystalline cellulose 105, colloidal anhydrous silicon dioxide,
sodium croscarmellose, sodium lauryl sulfate, hydrogenated vegetable oil, hypromellose 2910, propylene glycol, titanium dioxide (E 171), talc.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

for 250 mg tablets: white, capsule-shaped, biconvex film-coated tablets with a break line on one side, core diameter 8x14 mm;

for 500 mg tablets: white, capsule-shaped, biconvex film-coated tablets with break lines on both sides, core diameter 9x19 mm.

The break line is intended only to facilitate breaking for ease of swallowing, and not for dividing into equal doses.

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 the inhibition of microbial cell wall synthesis.

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

Cefuroxime is generally active in vitro 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 of the latter, and enters the bloodstream as cefuroxime. Optimal absorption is observed immediately after food intake. Maximum serum concentration of cefuroxime is reached approximately 2–3 hours after drug administration. The elimination half-life of the drug is approximately 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.

Axetin**®** 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 susceptible 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 other types 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 cefuroxime axetil and may eliminate the enhanced absorption effect observed after food intake.

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

Since a pseudonegative result may occur in the ferricyanide test, glucose oxidase or hexokinase methods are recommended for determining glucose levels in blood and plasma in patients receiving cefuroxime axetil. Cefuroxime does not interfere with the alkaline picrate method 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 international normalized ratio (INR).

Serum cefuroxime levels are reduced by dialysis.

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

Special precautions for use.

Hypersensitivity reactions. As with other beta-lactam antibiotics, severe and occasionally fatal hypersensitivity reactions have been reported. Hypersensitivity reactions progressing to Kounis syndrome – acute allergic coronary artery spasm, which may lead to myocardial infarction – have also been reported (see section "Adverse reactions"). In case of severe hypersensitivity reactions, treatment with Aksétin**®** must 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 medicinal products. Cefuroxime should be administered with caution to patients with a history of mild hypersensitivity reactions to other beta-lactam medicinal products.

Severe cutaneous adverse reactions (SCARs). Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and 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 about the signs and symptoms of SCARs and carefully monitored for skin reactions during treatment. If signs or symptoms suggestive of these reactions occur, cefuroxime should be discontinued immediately and alternative therapy considered. Cefuroxime must never be re-administered to patients who have experienced a serious reaction such as SJS, TEN, or DRESS syndrome during treatment.

Overgrowth of non-susceptible microorganisms. The use of cefuroxime axetil (as with other antibiotics) may result in overgrowth of Candida. Prolonged treatment may also lead to overgrowth of other non-susceptible microorganisms (e.g., Enterococci, Clostridium difficile), which in turn may necessitate discontinuation of therapy.

Pseudomembranous colitis, ranging from mild to life-threatening forms, may occur during or after antibiotic therapy. Therefore, it is important to consider this possibility in patients who develop severe diarrhea during or after antibacterial treatment. If prolonged or pronounced diarrhea occurs, or if the patient experiences severe colicky abdominal pain, treatment should be discontinued immediately and a thorough medical evaluation should be performed.

Jarisch–Herxheimer reaction. The Jarisch–Herxheimer reaction has been observed during treatment of Lyme disease with cefuroxime axetil, due to the bactericidal effect of cefuroxime axetil on Borrelia burgdorferi, the spirochete causing Lyme disease. Patients should be informed that this is a common consequence of antibiotic therapy for Lyme disease and resolves without treatment.

In sequential therapy, the timing of transition 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. Before initiating sequential therapy, the relevant Instructions for Use for sodium cefuroxime should be consulted. Aksétin**®** tablets contain propylene glycol, which may cause symptoms similar to those produced by alcohol consumption.

The medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy. Data on the use of cefuroxime in pregnant women are limited. Animal studies have not shown any adverse effects of cefuroxime axetil on pregnancy, embryonal or fetal development, parturition, or postnatal development. Aksétin**®** should be administered to pregnant women only when the potential benefit justifies the potential risk to the fetus.

Breastfeeding. Cefuroxime is excreted in breast milk in small amounts. With therapeutic doses, adverse reactions in the infant are not expected, but the risk of diarrhea or fungal mucosal infections cannot be excluded. Therefore, discontinuation of breastfeeding may be necessary due to these potential reactions. The possible sensitizing effect of the medicinal product should also be considered. Cefuroxime may be used during breastfeeding only after a physician has evaluated the benefit-risk balance of its use.

Fertility. There are no data on the effect of cefuroxime axetil on human fertility. In animal reproductive studies, no effects on fertility were observed.

Ability to affect reaction speed when driving or operating machinery.

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

Dosage and Administration

Sensitivity to the antibiotic varies depending on the region and may change over time. Local data on antibiotic sensitivity should be consulted when necessary.

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

To ensure optimal absorption, the drug should be taken after meals.

Dosage for adults and children according to infection type is provided in Tables 1 and 2.

Adults and children (≥ 40 kg)

Table 1

Children (< 40 kg)

Table 2

It is recommended to prescribe the drug in the form of a suspension for children. Cefuroxime axetil tablets and cefuroxime axetil granules for the preparation of a suspension are not bioequivalent; therefore, these dosage forms are not interchangeable when converting doses to milligrams.

Cefuroxime is also available as a sodium salt for parenteral administration. This allows sequential therapy with a single antibiotic when switching from parenteral to oral administration, if there are clinical indications for this. Axetin**®** is effective for sequential treatment of exacerbations of chronic bronchitis following prior parenteral administration of cefuroxime sodium.

Sequential therapy. Exacerbations of chronic bronchitis: 750 mg cefuroxime 2–3 times daily (intravenously or intramuscularly) for 48–72 hours, followed by oral administration of Axetin**®** 500 mg twice daily for 5–10 days. The duration of both parenteral and oral treatment should be determined based on the severity of infection and the patient's condition.

Patients with renal impairment

Cefuroxime is primarily eliminated by the kidneys. In patients with marked impairment of renal function, the dose of cefuroxime should be reduced to compensate for its slower excretion (see table below).

Patients with hepatic impairment. There are no data on the use of this medicinal product in patients with hepatic dysfunction. Cefuroxime is primarily eliminated by the kidneys, therefore, hepatic impairment is not expected to affect the pharmacokinetics of cefuroxime.

Children.

There is no experience with the use of cefuroxime axetil for the treatment of children under 3 months of age. The suspension formulation is recommended for administration to children.

Overdose.

CNS irritation and neurological complications, including encephalopathy, seizures, and coma, may occur in cases of cephalosporin overdose. Symptoms of overdose may occur if the drug dose has not been appropriately adjusted in patients with impaired renal function (see sections "Dosage and administration" and "Special warnings"). 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 mostly reversible. The adverse reactions listed below are classified by organ systems and frequency of occurrence. Frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000), very rare (< 1/10,000).

Infections and infestations.
Common: overgrowth of Candida.
Unknown frequency: overgrowth of Clostridium difficile.

Blood and lymphatic system disorders.
Common: eosinophilia.
Uncommon: positive Coombs test, thrombocytopenia, leukopenia (sometimes profound).
Very rare: hemolytic anemia.

Cephalosporins as a class may adsorb to the surface of red blood cell membranes and interact with antibodies, potentially leading to a positive Coombs test (which may interfere with blood compatibility testing) and, very rarely, to hemolytic anemia.

Cardiac disorders.
Unknown frequency: Kounis syndrome.

Immune system disorders.
Hypersensitivity reactions, including:
Uncommon: skin rash;
Rare: urticaria, pruritus;
Very rare: drug fever, serum sickness, anaphylaxis;
Unknown frequency: Jarisch–Herxheimer reaction.

Nervous system disorders.
Common: headache, dizziness.

Gastrointestinal disorders.
Common: gastrointestinal disturbances, including diarrhea, 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).
Very rare: jaundice (mainly cholestatic), hepatitis.

Skin and subcutaneous tissue disorders.
Very rare: erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis (exanthematous necrolysis).
Unknown frequency: angioneurotic edema, drug-induced eosinophilia with systemic symptoms (DRESS syndrome).

Children.
The safety profile of cefuroxime in pediatric patients is consistent with that observed in adults.

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

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 30 °C, in the original packaging, in a place inaccessible to children.

Packaging. 10 tablets in a strip, 1 strip per cardboard box; 10 tablets in a blister, 1 blister per cardboard box.

Prescription category. Prescription only.

Manufacturer. Medochemie Limited.

Manufacturer's address and location of operations.
Agios Athanassios Industrial Area, Michail Irakleous 2, Agios Athanassios, Limassol, 4101, Cyprus / Agios Athanassios Industrial Area, Michail Irakleous 2, Agios Athanassios, Limassol, 4101, Cyprus.