Xynthal

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KSYNFAL

Composition:

Active substance: cefixime;

1 film-coated tablet contains 447.68 mg of cefixime trihydrate, equivalent to 400 mg of cefixime;

Excipients: calcium hydrogen phosphate, anhydrous; pregelatinized starch (corn starch); hydroxypropylcellulose; purified water; isopropyl alcohol; microcrystalline cellulose (PH-112); magnesium stearate; film coating: Opadry AMB White OY-B-28920 (partially hydrolyzed polyvinyl alcohol, titanium dioxide (E 171), talc (E 553b), lecithin (soy) (E 322), xanthan gum (E 415)), purified water.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, white to almost white, capsule-shaped, with beveled edges, marked with "E" and a break line on one side, and "8" and "7" separated by a break line on the other side.

Pharmacotherapeutic group. Third-generation cephalosporins.

ATC code J01D D08.

Pharmacological properties.

Pharmacodynamics.

Cefixime is an oral third-generation cephalosporin with pronounced bactericidal activity in vitro against a broad spectrum of gram-positive and gram-negative microorganisms.

Clinical efficacy has been demonstrated in infections caused by common pathogens, including Streptococcus pneumoniae, Streptococcus pyogenes, Escherichia coli, Proteus mirabilis, Klebsiella species, Haemophilus influenzae (both beta-lactamase-producing and non-producing strains), Branhamella catarrhalis (both beta-lactamase-producing and non-producing strains), and Enterobacter species. Cefixime is highly stable in the presence of beta-lactamase enzymes.

Most strains of enterococci (Streptococcus faecalis, group D streptococci) and staphylococci (including both coagulase-positive and coagulase-negative strains, as well as methicillin-resistant strains) are resistant to cefixime. In addition, most strains of Pseudomonas, Bacteroides fragilis, Listeria monocytogenes, and Clostridia are resistant to cefixime.

Pharmacokinetics.

Absolute oral bioavailability of cefixime ranges from 22% to 54%. Food intake does not significantly affect absorption. Therefore, cefixime can be administered independently of food intake.

According to in vitro studies, serum or urine concentrations of cefixime at or above 1 mcg/mL are considered adequate for most common pathogens to which it is active.

Typically, maximum serum concentrations after administration of recommended doses for adults or children range from 1.5 to 3 mcg/mL. Accumulation of cefixime after repeated dosing has not been observed or was minimal.

In healthy elderly and young volunteers, pharmacokinetics of cefixime were compared after administration of 400 mg once daily for 5 days. Mean Cmax and AUC values were slightly higher in elderly subjects. Elderly patients can be administered the same dose as used in the general patient population (see section "Dosage and administration").

Cefixime is primarily excreted unchanged in urine. Glomerular filtration is considered the predominant mechanism. Metabolites of cefixime have not been identified in human serum or urine.

Cefixime is almost exclusively bound to the albumin fraction, with the free fraction averaging approximately 30%. Protein binding of cefixime is dependent on serum concentration in humans only at very high concentrations not achieved under normal clinical dosing.

The amount of 14C-labeled cefixime transferred through breast milk from female rats to offspring was low (approximately 1.5% of the cefixime content in females reached the offspring). Data on secretion of cefixime into human breast milk are lacking. Placental transfer of cefixime in pregnant female rats administered labeled cefixime was minimal.

Clinical characteristics.

Indications.

Cefixime is an oral active cephalosporin antibiotic exhibiting pronounced bactericidal activity in vitro against a broad spectrum of gram-positive and gram-negative microorganisms.

It is indicated for the treatment of the following acute infections caused by susceptible microorganisms:

• Infections of the upper respiratory tract (e.g., otitis media) and other upper respiratory tract infections when resistance of the causative agent to other commonly used antibiotics is known or suspected, or when there is a risk of treatment failure.
• Infections of the lower respiratory tract (e.g., bronchitis).
• Urinary tract infections (e.g., cystitis, cystourethritis, uncomplicated pyelonephritis).

Cefixime is clinically effective in treating infections caused by the most common pathogenic microorganisms, including Streptococcus pneumoniae, Streptococcus pyogenes, E. coli, Proteus mirabilis, Klebsiella species, Haemophilus influenzae (strains producing and non-producing beta-lactamase), Branhamella catarrhalis (strains producing and non-producing beta-lactamase), and Enterobacter species. It has a high degree of stability in the presence of beta-lactamases.

Most strains of enterococci (Streptococcus faecalis, Streptococci group D) and Staphylococci (including coagulase-positive, coagulase-negative, and methicillin-resistant strains) are resistant to cefixime. In addition, most strains of Pseudomonas, Bacteroides fragilis, Listeria monocytogenes, and Clostridia are resistant to cefixime.

Contraindications.

Hypersensitivity to the active substance, other cephalosporin antibiotics, or any of the excipients.

Interaction with other medicinal products and other forms of interaction.

Anticoagulants

As with other cephalosporins, prolonged prothrombin time has been observed in some patients. Therefore, caution is advised in patients receiving anticoagulant therapy.

Cefixime should be administered with caution to patients receiving coumarin-type anticoagulants, such as warfarin potassium. Since cefixime may potentiate the effect of anticoagulants, prolonged prothrombin time with or without bleeding may occur.

Other forms of interaction

Benedict's or Fehling's solutions or copper sulfate test tablets may give a false-positive reaction when testing urine for glucose; however, such reactions are not observed when using enzymatic glucose oxidase-based tests.

A false-positive direct Coombs' test has been reported during treatment with cephalosporin antibiotics; therefore, it should be noted that a positive Coombs' test may be due to such medications.

Special precautions for use.

Encephalopathy

Beta-lactams, including cefixime, may increase the risk of encephalopathy (which may include convulsions, confusion, impaired consciousness, and motor disturbances) in patients, particularly in cases of overdose and renal impairment.

Severe skin adverse reactions

Severe skin adverse reactions have been reported during cefixime therapy, such as toxic epidermal necrolysis, Stevens–Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), and acute generalized exanthematous pustulosis. Patients should be informed about the signs and symptoms of serious skin reactions and monitored closely. Treatment should be discontinued at the first appearance of skin rash, mucosal lesions, or any other signs of skin hypersensitivity.

Cefixime should be administered with caution in patients who have experienced hypersensitivity reactions to other drugs.

Hypersensitivity to penicillins

As with other cephalosporins, cefixime should be used cautiously in patients with a history of penicillin hypersensitivity, as there is some evidence of partial cross-allergenicity between penicillins and cephalosporins.

Severe reactions (including anaphylaxis) have been observed in patients treated with both classes of drugs. If an allergic reaction occurs during treatment with Ksinfal, the drug should be discontinued immediately, and appropriate therapy should be initiated as needed.

Hemolytic anemia

Cases of drug-induced hemolytic anemia, including severe cases with fatal outcomes, have been reported during cephalosporin therapy. Recurrence of hemolytic anemia after re-administration of cephalosporins has also been reported in patients with a history of cephalosporin-associated hemolytic anemia (including cefixime).

Acute renal failure

The use of cephalosporins, including cefixime, may lead to acute renal failure, with tubulointerstitial nephritis being the primary pathological condition. If acute renal failure occurs, cefixime should be discontinued and appropriate therapy and/or measures should be initiated.

Renal function impairment

Ksinfal should be administered with caution in patients with severe renal function impairment.

Use in children

The safety of cefixime use in premature or newborn infants has not been established.

Antibiotic-associated colitis

Treatment with broad-spectrum antibiotics may disrupt the normal intestinal microflora, potentially leading to overgrowth of Clostridium difficile, which produces toxins and is a major cause of antibiotic-associated diarrhea. Pseudomembranous colitis has been associated with the use of broad-spectrum antibiotics (including macrolides, semisynthetic penicillins, lincosamides, and cephalosporins). Therefore, it is important to consider this diagnosis in patients who develop diarrhea during or after antibiotic therapy. Symptoms of pseudomembranous colitis may develop during or after discontinuation of antibiotic treatment.

Management of pseudomembranous colitis should include sigmoidoscopy, appropriate bacteriological testing, and repletion of fluids, electrolytes, and proteins. If symptoms do not improve after discontinuation of the drug or become severe, oral vancomycin should be administered. Vancomycin is the drug of choice for treating antibiotic-associated pseudomembranous colitis caused by C. difficile. Other causes of colitis should be excluded.

Use during pregnancy or breastfeeding

There are no adequate and well-controlled studies on the use of cefixime in pregnant women. Therefore, Ksinfal should not be used during pregnancy or breastfeeding unless considered necessary by the physician.

In reproductive studies in mice and rats, doses nearly 400 times higher than the human dose did not show any adverse effects on fertility or fetal development due to cefixime. In rabbits, doses nearly 4 times higher than the human dose showed no evidence of teratogenic effects; however, a high rate of abortions and maternal mortality was observed, which is an expected consequence of the known sensitivity of rabbits to antibiotic-induced changes in intestinal microflora.

Ability to affect reaction speed when operating vehicles or machinery

If adverse effects such as encephalopathy (which may include seizures, confusion, impaired consciousness, and motor disturbances) occur, the patient should not operate machinery or drive vehicles.

Dosage and Administration

The usual course of treatment is 7 days. If necessary, it can be extended up to 14 days.

Dosage

Adults and children aged 12 years or older, or weighing more than 50 kg

The recommended dose is 200–400 mg daily, depending on the severity of the infection, taken once daily or divided into two doses.

This medicinal product in this formulation and dosage is intended for use in children aged 12 years and older.

Children under 12 years of age

The medicinal product is not recommended for use in children under 12 years of age. The safety and efficacy of cefixime in children under 6 months of age have not been established.

Elderly patients

Elderly patients may receive the same dose as recommended for adult patients. Renal function should be assessed and dosage adjusted in cases of severe renal impairment (see below).

Renal impairment

The medicinal product can be administered in patients with impaired renal function. Patients with a creatinine clearance of 20 mL/min or higher may receive the standard dose and dosing regimen. For patients with a creatinine clearance below 20 mL/min, the dose should not exceed 200 mg once daily. The dosage and administration regimen for patients undergoing chronic ambulatory peritoneal dialysis or hemodialysis should be the same as for patients with a creatinine clearance below 20 mL/min.

Administration method

For oral use. The absorption of Xinfalu is not significantly altered by the presence of food.

Children

This medicinal product in this formulation and dosage is intended for use in children aged 12 years and older.

Overdose

When beta-lactam antibiotics, including cefixime, are used, there is a risk of encephalopathy, particularly in cases of overdose or impaired renal function.

Adverse reactions observed following administration of cefixime doses up to 2 g in healthy volunteers did not differ from the profile observed in patients receiving recommended doses. Cefixime is not substantially removed from the bloodstream by dialysis.

There is no specific antidote. General supportive measures are recommended.

Adverse Reactions

Cefixime is generally well tolerated. Most of the adverse reactions observed in clinical trials were mild and resolved spontaneously.

Listed below are adverse reactions reported during the use of cefixime.

Blood and lymphatic system disorders: eosinophilia, hyper-eosinophilia, agranulocytosis, leukopenia, neutropenia, granulocytopenia, hemolytic anemia, thrombocytopenia, thrombocytosis.

Gastrointestinal disorders: abdominal pain, diarrhea*, dyspepsia, nausea, vomiting, bloating.

Hepatobiliary disorders: jaundice.

Infections and infestations: pseudomembranous colitis, vaginitis.

Investigations: increased levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, urea, creatinine.

Nervous system disorders: dizziness, headache.

Seizures have been reported during treatment with cephalosporins, including cefixime (frequency unknown)**.

Beta-lactams, including cefixime, may lead to encephalopathy (which may include seizures, confusion, altered consciousness, movement disorders), particularly in cases of overdose or impaired renal function (frequency unknown)**.

Respiratory, thoracic and mediastinal disorders: dyspnea.

Renal and urinary disorders: acute renal failure with tubulointerstitial nephritis.

Immune system disorders: anaphylactic reactions, angioneurotic edema, serum sickness.

Skin and subcutaneous tissue disorders: drug rash with eosinophilia and systemic symptoms (DRESS), erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria, rash, pruritus, acute generalized exanthematous pustulosis.

General disorders and administration site conditions: drug fever, arthralgia, pyrexia, facial swelling, genital pruritus.

The adverse reactions listed above were observed during clinical trials and/or post-marketing use of cefixime.

*Diarrhea was more frequently associated with higher doses. Some cases of moderate to severe diarrhea have been reported; this may sometimes necessitate discontinuation of therapy. Cessation of Xinfal treatment is recommended if severe diarrhea occurs.

**Cannot be estimated from the available data.

Reporting of suspected adverse reactions.

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

Shelf life.

2 years.

Storage conditions.

Store at a temperature not exceeding 25 °C. Keep out of the reach of children.

Packaging.

10 tablets per blister, 1 blister per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Aurobindo Pharma Ltd Unit VI, Block D.

Manufacturer's address and location of operations.

Survey No. 329/39 and 329/47, Chitkul Village, Patancheru Mandal, Sangareddy District, Telangana State, 502307, India.