XYNTHAL

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CINFAL

Composition:

Active substance: cefixime;

One film-coated tablet contains 223.84 mg of cefixime trihydrate, equivalent to 200 mg of cefixime;

Excipients: calcium hydrogen phosphate anhydrous, pregelatinized starch, hydroxypropylcellulose, microcrystalline cellulose, magnesium stearate; film coating: "Opadry" AMB White OY-B-28920 (partially hydrolyzed polyvinyl alcohol, titanium dioxide (E 171), talc, soy lecithin, xanthan gum).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, white or almost white, capsule-shaped, with beveled edges, marked with "E" and a break line on one side, and with markings "3" and "8" separated by a break line on the other side.

Pharmacotherapeutic group. Antibacterials for systemic use. Beta-lactam antibiotics. Third-generation cephalosporins. ATC code J01D D08.

Pharmacological Properties

Pharmacodynamics

The mechanism of action of cefixime, as with other cephalosporins, is based on the inhibition of bacterial cell wall synthesis. Cefixime exhibits bactericidal activity in vitro against many Gram-positive and Gram-negative microorganisms.

ANTIBACTERIAL SPECTRUM OF ACTIVITY

The concentration breakpoints that separate susceptible strains from those with intermediate susceptibility, and the latter from resistant strains, are: S ≤ 1 mg/L and R > 2 mg/L.

The prevalence of acquired resistance may vary geographically and over time for certain species. Therefore, information on local resistance patterns is useful, especially when treating severe infections. Such data can only provide guidance regarding the likely susceptibility of a bacterial strain to an antibacterial agent.

The table below shows the known variability in the prevalence of resistance for the bacterial species in France.

Pharmacokinetics

Absorption. After oral administration of a single 200 mg dose, the maximum serum concentration (Cmax) averages 3 µg/mL and is reached (Tmax) approximately within 3–4 hours.

After administration of a 400 mg dose, serum maximum concentrations are higher (3.4–5 µg/mL), but not proportionally increased relative to the dose.

Following repeated administration over 15 days of 400 mg/day as either single or divided doses, serum concentrations and bioavailability remain unchanged, indicating no accumulation of the active substance.

The bioavailability of cefixime is approximately 50% at a 200 mg dose. This parameter is not altered by food intake. However, the time to reach peak serum concentrations is delayed by approximately one hour when taken with food.

Distribution. The apparent volume of distribution is approximately 15 liters. In animals, cefixime diffuses into most of the tissues studied, except the brain. In humans, after administration of 200 mg doses at 12-hour intervals, lung tissue concentrations at 4 and 8 hours after the last dose are approximately 1 µg/g of tissue, with these concentrations exceeding the MIC90 for susceptible microorganisms responsible for pulmonary infections.

Elimination. The elimination half-life (T½) ranges from 3 to 4 hours (mean 3.3 hours). The drug is excreted unchanged by the kidneys (16–20% of the administered dose), while non-renal elimination occurs primarily via bile (25%).

No metabolites have been detected in serum or urine in either animals or humans.

In cases of severe renal impairment (creatinine clearance < 20 mL/min), the prolonged elimination half-life from plasma and increased maximum serum concentrations necessitate a reduction in the daily dose from 400 mg to 200 mg/day.

In hepatic insufficiency, elimination is slowed (T½ = 6.4 hours), but dosage adjustment is not required.

Protein binding to serum proteins is approximately 70%, occurring predominantly with albumin, and is independent of concentration (within therapeutic doses).

Cefixime pharmacokinetics are only minimally altered in elderly individuals. A slight increase in peak serum concentration, bioavailability, and a minor reduction in the amount excreted (by 15–25%) do not require dose reduction in this population.

Clinical Characteristics

Indications

For use in children aged 12 years and older and adults with bacterial infections caused by microorganisms sensitive to the drug, when such infections permit oral antibiotic therapy, specifically:

• Acute pyelonephritis without uropathy.

• Bacterial superinfections in acute bronchitis and exacerbations of chronic bronchitis.

• Bacterial pneumonias.

• Sinusitis and acute otitis media.

• Gonococcal urethritis in males.

• Complicated or uncomplicated urinary tract infections, excluding prostatitis.

Official guidelines on appropriate use of antibiotics should be taken into account.

Contraindications. Hypersensitivity to cephalosporin antibiotics or to any other component of the medicinal product; hypersensitivity to penicillins; porphyria.

Interaction with other medicinal products and other forms of interaction

Clinically significant interactions have not been reported during clinical studies.

Pharmacokinetic studies have shown that co-administration of 1 g of probenecid with cefixime reduces total cefixime clearance by 25%. In humans, antacid agents do not reduce cefixime absorption.

Cefixime enhances the nephrotoxicity of aminoglycosides.

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

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

Coumarin-type anticoagulants. Cefixime should be used with caution in patients receiving coumarin-type anticoagulants, such as warfarin. Since cefixime may potentiate the effects of anticoagulants, an increase in prothrombin time is possible, with or without clinical signs of bleeding.

Carbamazepine, when administered concurrently with cefixime, may lead to increased plasma concentrations of the latter; therefore, monitoring of carbamazepine plasma levels is advisable.

Nifedipine increases the bioavailability of cefixime.

Furosemide and aminoglycosides enhance the nephrotoxicity of the drug.

When using cefixime, as with other antibiotics, reduced reabsorption of estrogens and decreased effectiveness of combined oral contraceptives may occur.

False-positive reactions in urine ketone tests (nitroprusside method) have been reported. Cefixime may cause pseudopositive results in tests for glucose in urine when using copper sulfate, such as Benedict's or Fehling's solutions, or with Clinitest tablets. The drug does not affect methods based on enzymatic oxidation reactions. False-positive results in the direct Coombs test may occur during cefixime therapy.

Cases of increased activity of oral anticoagulants have been reported in patients receiving antibiotics. Risk factors include severe infectious or inflammatory conditions, advanced age, and overall patient condition. Under these circumstances, it may be difficult to distinguish the effect of the infectious disease from the effect of the drugs used to treat it on INR (International Normalized Ratio) imbalance. However, certain classes of antibiotics (fluoroquinolones, macrolides, tetracyclines, co-trimoxazole, and some cephalosporins) have a greater impact.

Special precautions for use

Warning

Any allergic manifestations require immediate discontinuation of treatment.

Prescribing cephalosporins requires prior evaluation. Allergy to penicillins cross-reacts with allergy to cephalosporins in 5–10% of cases.

Administration of cephalosporins to patients sensitive to penicillin requires extreme caution; strict medical supervision is necessary from the first dose.

Cephalosporins must never be prescribed to patients with a history of immediate-type allergy to cephalosporins. In doubtful cases, a physician must be present during the first administration of the drug to manage a possible anaphylactic reaction.

Renal impairment. Cefixime should be administered with caution to patients with significantly impaired renal function. Like other cephalosporins, cefixime may lead to acute renal failure, including tubulointerstitial nephritis as the primary pathological condition. If acute renal failure occurs, cefixime should be discontinued and appropriate therapy or measures initiated.

Hypersensitivity reactions (anaphylaxis). The drug should be prescribed cautiously to patients with a history of allergic reactions, particularly to penicillins, cephalosporins, and other medicinal products. Severe reactions (including anaphylactic reactions and cross-allergic reactions) have been reported in some patients. If an allergic reaction to cefixime occurs, the drug should be discontinued immediately and appropriate treatment initiated.

Severe cutaneous adverse reactions have occurred in patients receiving cefixime, such as drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) or bullous skin reactions (toxic epidermal necrolysis, Stevens-Johnson syndrome, Lyell’s syndrome, and acute generalized exanthematous pustulosis). In case such reactions occur, cefixime administration should be stopped immediately.

Gastrointestinal tract (GI tract). Precautions are necessary when administering the drug to patients with a history of gastrointestinal disorders, particularly colitis (cases of pseudomembranous colitis have been reported).

Broad-spectrum antibiotics disrupt the normal flora of the colon and may lead to rapid overgrowth of clostridia. The toxin produced by Clostridium difficile is the main cause of antibiotic-associated diarrhea.

Cases of colitis associated with antibacterial agents, including pseudomembranous colitis, have been reported with nearly all antibacterial agents, including cefixime, with severity ranging from mild to life-threatening. Therefore, this diagnosis must be considered in patients who develop diarrhea during or after cefixime treatment. Discontinuation of cefixime and initiation of specific therapy for Clostridium difficile should be considered. The use of any peristalsis inhibitors should be avoided.

Prolonged use of the drug may disrupt the normal intestinal flora, potentially leading to overgrowth of Candida albicans and, consequently, oral mucosal candidiasis. Severe diarrhea and pseudomembranous colitis may also occur. Symptoms of pseudomembranous colitis may develop during or after antibiotic treatment. A positive direct Coombs' test and false-positive urine glucose test may occur during treatment. If relevant symptoms occur, cefixime treatment should be discontinued and appropriate investigations and therapy initiated.

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

Anemia. Cases of hemolytic anemia, including severe cases with fatal outcomes, have been reported after cephalosporin use. Recurrent episodes of hemolytic anemia after cephalosporin administration have also been documented in patients who previously developed hemolytic anemia following initial cephalosporin exposure, including cefixime. If anemia develops during cefixime treatment, cefixime-associated anemia should be considered, and cefixime should be discontinued until the etiology is established.

Encephalopathy. When beta-lactam antibiotics, including cefixime, are administered, there is a risk of encephalopathy (which may include seizures, confusion, altered consciousness, or abnormal movements), particularly in cases of overdose or impaired renal function.

Special precautions for use

In patients with allergy to other beta-lactam antibiotics, cross-reactivity should be considered.

In cases of severe renal impairment, dose adjustment of the drug may be necessary.

Use during pregnancy or breastfeeding. The drug may be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus. Although clinical data are limited, animal studies have not shown teratogenic or fetotoxic effects.

It is unknown whether cefixime is excreted in human breast milk. If cefixime must be administered to a woman during lactation, breastfeeding should be discontinued.

Ability to influence reaction speed when driving or operating machinery. The drug does not affect reaction speed; however, due to the possibility of adverse reactions such as encephalopathy (which may include seizures, confusion, altered consciousness, or abnormal movements), patients should not drive or operate machinery.

Dosage and Administration

The medicinal product is intended for use in children aged 12 years and older, as well as adults.

Dosage

Adults and children aged 12 years and older

The dose of cefixime is 400 mg per day (two doses of 200 mg each, administered at 12-hour intervals).

For gonococcal urethritis, efficacy is achieved with a single dose of two 200 mg tablets.

Elderly patients do not require dose adjustment provided renal function is normal.

Patients with impaired renal function

If creatinine clearance exceeds 20 ml/min, dose adjustment is not necessary. In patients with lower values, including those undergoing hemodialysis, the daily dose of cefixime should not exceed 200 mg administered once daily.

Patients with impaired hepatic function do not require dose adjustment.

Administration: Oral.

Children. Cefixime in this pharmaceutical form and dosage is indicated for children aged 12 years and older.

Overdose

Symptoms: Leukopenia, thrombocytopenia, acute hemolytic anemia, skin reactions, dyspnea, stomatitis, anorexia, temporary hearing loss, renal failure, diarrhea, encephalopathy.

Treatment: Gastric lavage, administration of antihistamines, symptomatic therapy. There is no specific antidote. Hemodialysis and peritoneal dialysis do not effectively remove the drug from plasma.

Adverse Reactions

Classification of frequency of adverse reactions: very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10000, < 1/1000); very rare (< 1/10000).

Blood and lymphatic system disorders: very rare — reversible thrombocytosis, thrombocytopenia, leukopenia, eosinophilia, neutropenia, and agranulocytosis (isolated cases of blood coagulation disorders have been reported); hyper-eosinophilia, hypoprothrombinemia, granulocytopenia, hemolytic anemia, thrombophlebitis, prolonged thrombin and prothrombin time, purpura; frequency not known — thrombocytosis.

Nervous system disorders: uncommon — headache, dizziness; dysphoria, hyperactivity.

Seizures have been reported during treatment with cephalosporins, including cefixime.

There is a risk of developing encephalopathy (which may include seizures, confusion, altered consciousness, or pathological movements) in cases of overdose or when the drug is administered to patients with impaired renal function.

Gastrointestinal disorders: uncommon — diarrhea and change in bowel habits, abdominal pain, dyspepsia, flatulence, nausea and vomiting; rare — transient elevations in liver transaminases or alkaline phosphatase; very rare — cases of pseudomembranous colitis, hepatitis, jaundice; gastric spasms, dysbacteriosis, oral candidiasis, stomatitis, glossitis.

Renal and urinary disorders: very rare — transient increase in serum urea or creatinine levels; acute renal failure, including interstitial nephritis as the primary pathological condition, hematuria.

Immune system disorders: rare — hypersensitivity reactions — allergic reactions such as rashes, pruritus, drug fever, and arthralgia, including isolated cases of urticaria or angioneurotic edema (reactions usually resolve after discontinuation of therapy); fever, facial swelling; very rare — Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

Metabolism and nutrition disorders: very rare — anorexia.

Ear and labyrinth disorders: rare — hearing loss.

Respiratory system disorders: rare — dyspnea.

Laboratory findings: most laboratory changes are transient and of no clinical significance. Possible increases in aspartate aminotransferase, alanine aminotransferase, serum bilirubin, blood urea, and serum creatinine levels.

Reproductive system and breast disorders: rare — genital pruritus, vaginitis, and moniliasis.

General disorders: frequency not known — weakness, fatigue, increased sweating, mucosal inflammation, fever.

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

Reporting of adverse reactions after drug registration is highly important. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should 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 below 25 °C. Keep out of reach of children.

Packaging. 10 tablets in a blister pack, 1 blister pack in a cardboard box.

Prescription category. Prescription only.

Manufacturer. Aurobindo Pharma Ltd Unit VI, Block D / Aurobindo Pharma Ltd Unit VI, Block D.

Manufacturer's address and location of business activity.

Sy. No. 329/39 & 329/47, Chitkul Village, Patancheru Mandal, Sanga Reddy District, Telangana State, 502307 India / Sy. No. 329/39 & 329/47, Chitkul Village, Patancheru Mandal, Sanga Reddy District, Telangana State, 502307 India.