Insim – 400

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT INCIM–400 (INCIM–400)

Composition:

Active substance: cefixime;

One film-coated tablet contains 400 mg of cefixime (as cefixime trihydrate);

Excipients: microcrystalline cellulose, pregelatinized starch, hydroxypropylcellulose, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate, coating agent Instacoat Universal IC-U-1308 White;

Composition of coating Instacoat Universal IC-U-1308 White: hypromellose, polyethylene glycol, talc, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: bilaterally convex, elongated-shaped tablets, film-coated, white to almost white in color.

Pharmacotherapeutic group. Antibacterials for systemic use. Other beta-lactam antibiotics. Third-generation cephalosporins. ATC code J01DD08.

Pharmacological properties.

Pharmacodynamics.

Cefixime is a third-generation cephalosporin antibiotic for oral administration. In vitro, it exhibits significant bactericidal activity against a broad spectrum of Gram-positive and Gram-negative microorganisms.

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), Branhamella catarrhalis (beta-lactamase-positive and negative), and Enterobacter species. It demonstrates high 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 also resistant to cefixime.

Pharmacokinetics.

Absorption. Absolute bioavailability after oral administration of cefixime ranges from 22% to 54%. Since food does not significantly affect absorption, cefixime can be administered regardless of food intake. Peak serum concentrations after administration of recommended doses in adults or children range from 1.5 to 3 mcg/mL. With repeated dosing, slight accumulation of cefixime may occur.

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

Metabolism. Metabolites of cefixime have not been isolated from human serum or urine.

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

There are no data on 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 treatment inefficacy;
• infections of the lower respiratory tract (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), 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, 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.

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

Interaction with other medicinal products and other types of interactions.

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

Salicylic acid increases 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 concentrations of carbamazepine; therefore, monitoring of plasma carbamazepine levels is advisable.

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

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

Potentially, similar to other antibiotics, use of the drug may lead to reduced efficacy of combined oral contraceptives.

Antacids containing magnesium or aluminum hydroxide delay absorption of the drug.

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 used with caution in patients receiving coumarin-type anticoagulants, such as potassium warfarin. Since cefixime may potentiate the effects of anticoagulants, an increase in prothrombin time with or without clinical signs of bleeding may occur.

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

Special precautions for use.

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

Severe skin adverse reactions such as toxic epidermal necrolysis, Stevens-Johnson syndrome, and drug reaction 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 immediately and appropriate therapy initiated.

Prior to initiating cefixime therapy, patients' medical history should be carefully evaluated for hypersensitivity reactions to penicillins, cephalosporins, or other drugs.

Cefixime should be administered with caution to patients with a history of allergic reactions to penicillins. In vivo and in vitro studies have demonstrated cross-allergic reactions between penicillins and cephalosporins. Such cases are rare but may occur in an anaphylactic pattern, particularly following parenteral administration.

Antibiotics should be used with caution in patients with a history of any type of hypersensitivity reactions, especially following drug administration. If an allergic reaction occurs, the drug should be discontinued immediately and appropriate therapy initiated.

Cases of drug-induced hemolytic anemia, including severe cases with fatal outcomes, have been reported during treatment with cephalosporins. Hemolytic anemia has also been reported following re-administration of cephalosporins, including cefixime.

Cefixime should be used with caution in patients with significant renal impairment (see "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.

Caution should be exercised when prescribing the drug to patients with a history of bleeding disorders, gastrointestinal diseases, particularly ulcerative colitis, regional enteritis, or antibiotic-associated colitis, as well as in patients with impaired liver function.

Prolonged use of antibacterial agents may lead to overgrowth of resistant microorganisms and disruption of normal intestinal flora, potentially resulting in overgrowth of Clostridium difficile and development of pseudomembranous colitis. In mild cases of pseudomembranous colitis associated with antibiotic use, discontinuation of the drug may be sufficient. If colitis symptoms do not improve after discontinuation, oral vancomycin, the antibiotic of choice for pseudomembranous colitis, should be administered.

In cases of moderate to severe colitis, treatment should include electrolyte and protein solutions. Concomitant use of drugs that reduce intestinal peristalsis should be avoided.

When cefixime is administered concomitantly with aminoglycosides, polymyxin B, colistin, or loop diuretics (furosemide, ethacrynic acid) at high doses, renal function should be closely monitored. After prolonged cefixime therapy, hematopoietic function should be evaluated.

A positive direct Coombs' test and false-positive urine glucose tests may occur during treatment.

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

Use during pregnancy or breastfeeding

Reproductive function studies in mice and rats receiving doses nearly 400 times higher than the human dose showed no evidence of effects on fertility or fetal abnormalities due to cefixime. In rabbits, at doses up to 4 times the human dose, no evidence of teratogenic effects was observed; however, a high incidence of abortions and maternal mortality occurred, which is an expected consequence of the known sensitivity of rabbits to antibiotic-induced changes in intestinal flora.

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

The drug should not be used during pregnancy or breastfeeding except in cases of extreme necessity and only if prescribed by a physician.

Ability to affect reaction speed when driving or operating machinery

Patients who experience central nervous system adverse reactions (e.g., seizures, dizziness, impaired consciousness, motor disturbances) while taking INCEM – 400 should refrain from driving or operating machinery.

Method of Administration and Dosage.

Food intake does not affect cefixime absorption. The usual duration of treatment is 7 days; if necessary, up to 14 days. For 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 tablet) once daily or 200 mg (half a tablet) every 12 hours, depending on the severity of the infection.

Elderly patients: administer the drug at the recommended adult dose. Renal function should be monitored and dosage adjusted in cases of severe renal impairment (see "Renal Impairment").

Renal impairment: cefixime can be used in patients with impaired renal function. For patients with creatinine clearance of 20 mL/min or higher, the usual dose and dosing regimen should be applied. For patients with creatinine clearance below 20 mL/min, the dose should not exceed 200 mg (half a tablet) once daily. This also applies to patients undergoing continuous ambulatory peritoneal dialysis or hemodialysis.

Children.

The use of the drug in another pharmaceutical form is recommended for children under 12 years of age.

Overdose.

There is a risk of encephalopathy when using beta-lactam antibiotics, including cefixime, especially in cases of overdose and renal impairment.

Adverse reactions observed with doses up to 2 g in healthy volunteers did not differ from those seen in patients receiving the drug at recommended doses.

Symptoms: intensification of adverse reactions.

Treatment: gastric lavage, symptomatic and supportive therapy. There is no specific antidote. Hemodialysis or peritoneal dialysis contributes only minimally to the elimination of cefixime from the body.

Adverse Reactions.

Blood and lymphatic system disorders: eosinophilia, hyper-eosinophilia, agranulocytosis, leukopenia, neutropenia, granulocytopenia, hemolytic anemia, thrombocytopenia, thrombocytosis, hypoprothrombinemia, thrombophlebitis, prolonged prothrombin and thrombin time, purpura.

Gastrointestinal disorders: stomach cramps, abdominal pain, diarrhea*, dyspepsia, nausea, vomiting, flatulence, dysbacteriosis, candidiasis of the oral mucosa, stomatitis, glossitis.

Hepatobiliary disorders: jaundice, hepatitis, cholestasis.

Infections and infestations: pseudomembranous colitis.

Laboratory findings: increased aspartate aminotransferase, increased alanine aminotransferase, increased blood bilirubin, increased blood urea, increased serum creatinine.

Metabolism and nutrition disorders: anorexia (loss of appetite).

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

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

Ear and labyrinth disorders: hearing loss.

Respiratory, thoracic and mediastinal disorders: dyspnea.

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

Immune system disorders: anaphylactic reaction, serum sickness-like reactions, drug fever, arthralgia.

Skin and subcutaneous tissue disorders: urticaria, skin rashes, pruritus, fever, facial swelling, angioneurotic edema, drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.

Reproductive system and breast disorders: genital pruritus, candidal vaginitis.

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

*Diarrhea is usually associated with higher doses of the drug. Cases of moderate to severe diarrhea have been reported. If severe diarrhea occurs, cefixime should be discontinued.

Shelf life.

2 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging.

Keep out of reach of children.

Packaging.

10 tablets per blister. 1 blister per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

Sens Laboratories Pvt. Ltd.

Manufacturer's address and place of business.

VI/51B, Post Box No. 2, Kozhuvanal, Pala, Kottayam – 686 573, Kerala, India.