Cefixime

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEFIX (CEFIX)

Composition:

Active substance: cefixime;

1 capsule contains cefixime (as trihydrate) 400 mg;

Excipients: microcrystalline cellulose, sodium lauryl sulfate, magnesium stearate, sodium croscarmellose, hydrogenated vegetable oil.

Capsule shell composition:

Capsule body: FD&C Blue No. 1 (E 133), titanium dioxide (E 171), gelatin, purified water;

Capsule cap: FD&C Blue No. 1 (E 133), titanium dioxide (E 171), gelatin, purified water.

Pharmaceutical form. Capsules.

Main physicochemical properties: white to yellowish powder in hard gelatin capsules with a blue cap marked «PhI» and a blue body marked «Cefix 400 mg», size 0E.

Pharmacotherapeutic group.

Antibacterials for systemic use. Other beta-lactam antibiotics. Third-generation cephalosporins. ATC code J01D D08.

Pharmacological properties.

Pharmacodynamics.

Cefixime is an oral third-generation cephalosporin antibiotic. In vitro, it demonstrates significant bactericidal activity against a broad spectrum of Gram-positive and Gram-negative microorganisms. It is clinically effective in the treatment of infections caused by the most common pathogenic microorganisms, including Streptococcus pneumoniae, Streptococcus pyogenes, E. coli, Proteus mirabilis, Klebsiella species, Haemophilus influenzae (beta-lactamase-positive and -negative), Moraxella (Branhamella) catarrhalis (beta-lactamase-positive and -negative), and Enterobacter species. It has a high degree of stability in the presence of beta-lactamases.

Most strains of enterococci (Streptococcus faecalis, group D streptococci) 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.

Pharmacokinetics.

Absorption. Absolute bioavailability after oral administration of cefixime ranges from 22% to 54%. Since the presence of food does not significantly affect absorption, cefixime can be administered regardless of food intake. The maximum serum concentration after administration of recommended doses in adults or children ranges from 1.5 to 3 mcg/mL. With repeated dosing, accumulation of cefixime is minimal or absent. The pharmacokinetics of cefixime were compared in healthy elderly patients (aged >64 years) and young volunteers (aged 11–35 years) after administration of 400 mg of cefixime once daily for 5 days. Mean Cmax and AUC values were slightly higher in elderly patients. Elderly patients can be administered the same dosage as adults.

Distribution. Cefixime is almost entirely bound to the albumin fraction, with the average free fraction being approximately 30%.

Metabolism. Metabolites of cefixime have not been identified in human serum or urine.

Elimination. Cefixime is excreted primarily unchanged in the urine. The predominant mechanism is glomerular filtration.

There are no data regarding the penetration of cefixime into breast milk.

Clinical characteristics.

Indications.

Infectious-inflammatory diseases caused by microorganisms sensitive to the drug:

• infections of the upper respiratory tract (including otitis media) and other upper respiratory tract infections (sinusitis, pharyngitis, tonsillitis of bacterial etiology) in cases of known or suspected resistance of the causative agent to other commonly used antibiotics, or in case of risk of ineffective treatment;
• lower respiratory tract infections (including acute bronchitis and exacerbations of chronic bronchitis);
• urinary tract infections (including cystitis, cystourethritis, uncomplicated pyelonephritis).

Clinically effective in the treatment of infections caused by the most common pathogenic microorganisms, including Streptococcus pneumoniae, Streptococcus pyogenes, E. coli, Proteus mirabilis, Klebsiella species, Haemophilus influenzae (beta-lactamase-positive and -negative), Moraxella (Branhamella) catarrhalis (beta-lactamase-positive and -negative), and Enterobacter species. Exhibits high stability in the presence of beta-lactamases.

Most strains of enterococci (Streptococcus faecalis, group D Streptococci) 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.

Confirmed hypersensitivity to cephalosporin antibiotics or to other components of the medicinal product; hypersensitivity to penicillins; porphyria.

Interaction with other medicinal products and other forms of interaction.

As with other cephalosporins, increased prothrombin time has been observed in some patients; therefore, caution should be exercised in patients receiving anticoagulant therapy.

Cefixime should be used with caution in patients receiving anticoagulants such as coumarins, for example potassium warfarin. Since cefixime may potentiate the effect of anticoagulants, an increase in prothrombin time with or without clinical signs of bleeding may occur.

Tubular secretion blockers (allopurinol, probenecid, diuretics) increase the maximum serum concentration of cefixime by slowing renal excretion of cefixime, which may lead to symptoms of overdose.

When cefixime is used concomitantly with potentially nephrotoxic substances (aminoglycosides, colistin, polymyxin, viomycin) or potent diuretics (ethacrynic acid, furosemide), there is an increased risk of developing renal failure.

Salicylic acid increases the level of free cefixime by 50% due to displacement of cefixime from protein-binding sites. This effect is concentration-dependent.

Concomitant use with carbamazepine may lead to increased plasma concentration of carbamazepine; therefore, monitoring of carbamazepine plasma levels is advisable.

Nifedipine increases the bioavailability of cefixime, but clinical interaction has not been established.

Use of the medicinal product may reduce reabsorption of estrogens and decrease the effectiveness of combined oral contraceptives.

During treatment with cefixime, false-positive glucose reactions in urine may occur when using copper sulfate tablets, Benedict's or Fehling's solutions. Glucose oxidase test is recommended for determination of glucose in urine.

Cephalosporin antibiotics may cause false-positive results in the direct Coombs' test. Therefore, it should be borne in mind that a positive Coombs' test result may be due to the use of this medicinal product.

Special precautions for use.

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

Severe skin adverse reactions, such as toxic epidermal necrolysis, Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms (DRESS syndrome), have been reported in some patients receiving cefixime. If severe skin adverse reactions occur, cefixime should be discontinued and appropriate treatment initiated.

Hemolytic anemia, including severe cases with fatal outcomes, has been reported during treatment with cephalosporins. Hemolytic anemia has also been reported following re-administration of cephalosporins (including cefixime).

Renal function.

Cefixime should be administered with caution in patients with significant renal impairment (see "Dosage and administration. Dosing in renal impairment").

As with other cephalosporins, cefixime may lead to acute kidney injury, including tubulointerstitial nephritis as the primary pathological condition. If acute kidney injury occurs, cefixime should be discontinued and appropriate therapy and/or measures initiated.

When cefixime is used at high doses concomitantly with aminoglycosides, polymyxin B, colistin, or loop diuretics (furosemide, ethacrynic acid), renal function should be closely monitored. Hematopoietic function should be checked after prolonged use of cefixime.

Hypersensitivity reactions.

Prior to initiating cefixime therapy, it is important to determine whether the patient has a history of hypersensitivity reactions to cephalosporins, penicillins, or other medicinal products.

Antibiotics, including cefixime, should be used with caution in patients with any type of allergic reaction, particularly to medicinal products.

If an allergic reaction occurs, the drug should be discontinued and appropriate treatment initiated. Allergic reactions (especially anaphylaxis) associated with beta-lactam antibiotics may be severe and, in rare cases, fatal (see "Adverse reactions").

Colitis / overgrowth of resistant microorganisms.

Adverse gastrointestinal reactions may occur during treatment; therefore, cefixime should be administered cautiously in patients with a history of gastrointestinal bleeding, gastrointestinal disorders (particularly ulcerative colitis, regional enteritis, or enteritis), and in those with impaired liver function.

Prolonged use of cefixime may lead to overgrowth of resistant microorganisms, including disruption of normal intestinal flora, which may result in overgrowth of Candida albicans and development of oral mucosal candidiasis (see "Adverse reactions").

Pseudomembranous colitis.

Broad-spectrum antibiotics, especially when used long-term, may lead to pseudomembranous colitis. Symptoms of pseudomembranous colitis may develop during or after antibiotic therapy.

The onset of severe diarrhea during treatment may indicate pseudomembranous colitis. In such cases, cefixime should be discontinued and appropriate diagnostic evaluation performed.

Effects on blood system.

Neutropenia and agranulocytosis may occur during treatment with beta-lactam antibiotics, particularly with prolonged therapy. If neutropenia develops, cefixime therapy should be discontinued.

Blood counts should be monitored during prolonged treatment (more than 10 days).

Effects on serological test results.

Cefixime may cause false-positive results in the Coombs test. Cefixime may also cause false-positive urine glucose tests (see "Adverse reactions").

Antibacterial spectrum.

In infections caused by group A beta-hemolytic streptococci, the treatment course should last at least 10 days to prevent acute rheumatic fever.

Interaction with alcohol.

Cephalosporins enhance the toxicity of alcohol; therefore, consumption of alcoholic beverages is not recommended during cefixime therapy.

Use during pregnancy or breastfeeding.

There are no data on the use of cefixime during pregnancy. Cefixime crosses the placenta.

Breastfeeding should be discontinued during treatment with cefixime.

The drug should not be used during pregnancy or breastfeeding except in cases of extreme necessity and only under a physician's prescription.

Ability to affect reaction speed when driving or operating machinery.

The possibility of central nervous system adverse reactions (e.g., dizziness) should be considered, as they may impair psychomotor performance. In such cases, patients should refrain from driving or operating machinery.

Method of Administration and Dosage

Food intake does not affect the absorption of cefixime. The duration of treatment depends on the severity of the disease and is determined individually. Typically, the treatment course lasts 7 days; if necessary, it may be extended to 14 days. In infections caused by Streptococcus pyogenes, the treatment course should be at least 10 days. For the treatment of uncomplicated cystitis, the treatment course is 3 days.

Adults and children aged 12 years and older with body weight over 50 kg:

The recommended dose is 400 mg (1 capsule) once daily.

For the treatment of uncomplicated urethral or cervical gonococcal infections, a single dose of 400 mg is recommended.

Elderly patients:

The drug should be administered at the standard adult dose. Renal function should be monitored, and dosage adjustment should be performed in cases of severe renal impairment (see "Dosage in Renal Impairment").

Dosage in Renal Impairment:

Cefixime should be administered with caution in patients with renal impairment. Dose adjustment should be based on creatinine clearance (CrCl). If CrCl is 60 mL/min or higher, administer the standard dose. If CrCl is between 21–60 mL/min or the patient is undergoing hemodialysis, administer 75% of the standard dose while maintaining the dosing intervals. If CrCl is less than 20 mL/min or the patient is undergoing peritoneal dialysis, administer ½ of the standard dose while maintaining the dosing intervals. Neither hemodialysis nor peritoneal dialysis significantly removes cefixime from the body.

If administration of a dose lower than 400 mg is required, it is recommended to use the drug in another pharmaceutical form (e.g., as a suspension).

Children:

For children under 12 years of age, it is recommended to use the drug in another pharmaceutical form.

Overdose.

Symptoms: intensification of adverse reactions, dizziness, nausea, vomiting, diarrhea.

Treatment: gastric lavage, administration of antihistamines and glucocorticoids; oxygen therapy. Hemodialysis or peritoneal dialysis only minimally enhance the elimination of cefixime from the body. Symptomatic therapy should be provided.

There are no specific antidotes for the treatment of cefixime overdose.

Adverse reactions.

Adverse reactions caused by cefixime are generally mild and occur infrequently. Possible disorders include:

Nervous system disorders: headache, dizziness, dysphoria; convulsions have been reported during treatment with cephalosporins, including cefixime (frequency unknown).

Beta-lactams, including cefixime, may increase the risk of encephalopathy (which may include convulsions, confusion, impaired consciousness, movement disorders) in patients, especially in cases of overdose and renal impairment (frequency unknown).

Ear and labyrinth disorders: hearing loss.

Respiratory system disorders: dyspnea.

Blood and lymphatic system disorders: eosinophilia, granulocytopenia, leukopenia, thrombocytopenia, thrombocytosis, neutropenia, hemolytic anemia, hypoprothrombinemia (bleeding and bruising without apparent cause), thrombophlebitis, prolonged thrombin and prothrombin time, agranulocytosis.

Gastrointestinal disorders: abdominal cramps, abdominal pain, diarrhea*, nausea, vomiting, oral candidiasis, pseudomembranous colitis, dry mouth, dyspepsia, flatulence, dysbacteriosis, in isolated cases – stomatitis, glossitis.

Metabolism and nutrition disorders: anorexia.

Hepatobiliary disorders: hepatitis, cholestasis, transient elevation of liver transaminases and alkaline phosphatase, hyperbilirubinemia, cholestatic jaundice, scleral icterus, skin icterus.

Renal and urinary system disorders: acute renal failure, including interstitial nephritis as the main pathological condition, hematuria.

Immune system, skin and subcutaneous tissue disorders: hypersensitivity reactions, including: rash, pruritus, angioneurotic edema, anaphylactic shock, anaphylactic reactions; serum sickness-like reactions; drug reaction with eosinophilia and systemic symptoms (DRESS); facial swelling, skin hyperemia, urticaria, erythema multiforme or Stevens-Johnson syndrome, serum sickness, purpura, arthralgia, fever, maculopapular and vesiculobullous rash, fungal dermatitis, epithelial desquamation, dry skin, hair loss, sunburn, toxic epidermal necrolysis.

Reproductive system and breast disorders: genital pruritus, Candida-induced vaginitis.

Infections and infestations: vaginal candidiasis (vaginal itching or discharge).

Cases of diarrhea following cefixime administration may be associated with Clostridium difficile.

Laboratory findings: most laboratory abnormalities are transient and clinically insignificant. Possible increases in blood urea nitrogen and serum creatinine levels, false-positive results in the Coombs test. A positive reaction for urinary ketones may occur in tests using sodium nitroprusside, but not nitroferricyanide. Cefixime intake may cause false-positive results in urine glucose tests (therefore, enzymatic tests should be used). Changes in liver and kidney function test parameters may also occur.

General disorders: increased sweating, increased fatigue, weakness, mucosal inflammation.

* Diarrhea is usually associated with higher doses of the drug. Cases of diarrhea (from moderate to severe) have been reported; in such cases, discontinuation of therapy is warranted. If severe diarrhea occurs, cefixime should be discontinued.

Reporting suspected adverse reactions after drug registration is highly important. Cases of suspected adverse reactions and lack of drug efficacy should be reported to a physician or through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

5 capsules in a blister; 1 blister per cardboard box.

Prescription status.

Prescription only.

Manufacturer/Marketing Authorization Holder.

Pharma International Company.

Manufacturer’s address and place of business.

Al Kastal area, Export road, P.O. Box 334 Jubaiha 11941, Amman – Jordan.

Address of the Marketing Authorization Holder.

P.O. Box 334 Al-Jubaiha 11941 Amman, Jordan.

Contact details of the manufacturer's/Marketing Authorization Holder's representative in Ukraine – LLC "Megakom":

195B Klochkivska Street, Kharkiv, 61145, Ukraine; phone: +38 (057) 701 37 55.