Flamifix 200

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FLAMIFIKS 200 (PHLAMIFIKS200)

Composition:

Active substance: cefixime;

One film-coated tablet contains cefixime trihydrate equivalent to anhydrous cefixime 200 mg;

Excipients: colloidal anhydrous silicon dioxide, microcrystalline cellulose, magnesium stearate, calcium sulfate, calcium hydrogen phosphate, lactose monohydrate, corn starch, sodium benzoate (E 211), talc, sodium starch glycolate (type A), hydroxypropylmethylcellulose, titanium dioxide (E 171), polyethylene glycol 6000.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: almost white, round, biconvex, film-coated tablets.

Pharmacotherapeutic group.

Antibacterials for systemic use. Beta-lactam antibiotics. Third-generation cephalosporins. ATC code J01DD08.

Pharmacological properties.

Pharmacodynamics.

Cefixime is a third-generation cephalosporin antibiotic intended for oral administration. 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 beta-lactamase-negative), Branhamella catarrhalis (beta-lactamase-positive and beta-lactamase-negative), and Enterobacter species. Cefixime exhibits 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. Additionally, 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 intake does not significantly affect absorption, cefixime can be administered regardless of food intake. According to in vitro studies, serum or urine concentrations of 1 mcg/mL are considered adequate for most common pathogens susceptible to cefixime. The maximum serum concentration after administration of recommended doses in adults or children ranges from 1.5 to 3 mcg/mL. With repeated dosing, there is minimal or practically no accumulation of cefixime.

Pharmacokinetics of cefixime were compared in 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 values of maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) were slightly higher in elderly patients. However, elderly patients can be administered the same dosage regimen as adults.

Distribution.

Protein binding of cefixime to serum proteins has been well characterized in both human and animal serum. Cefixime is almost entirely bound to the albumin fraction, with the mean free fraction being approximately 30%. Binding of cefixime to blood proteins depends only on serum concentration in humans at very high concentrations, which are not achieved following clinical dosing.

Metabolism.

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

Excretion.

Cefixime is excreted primarily unchanged in urine. The main mechanism is glomerular filtration.

Transfer of 14C-labeled cefixime from lactating rats to their offspring via milk was quantitatively low (approximately 1.5% of the maternal body content of cefixime transferred to offspring). There are no data on the excretion of cefixime into rat milk. Placental transfer of cefixime was minimal in pregnant rats administered radiolabeled cefixime.

Clinical characteristics.

Indications.

Treatment of bacterial infections caused by microorganisms sensitive to the drug:

• infections of the upper respiratory tract (pharyngitis, tonsillitis);
• otitis media;
• chronic bronchitis;
• uncomplicated urinary tract infections (cystitis, pyelonephritis).

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

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

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. As with other cephalosporins, increased 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 is possible.

Carbamazepine may cause an increase in plasma concentration of cefixime when administered concomitantly; therefore, monitoring of carbamazepine plasma levels is advisable.

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

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.

As with other antibiotics, cefixime may reduce estrogen reabsorption and decrease the effectiveness of combined oral contraceptives.

Other forms of interactions. The use of cephalosporins may lead to false-positive glucose in urine tests when using Benedict's or Fehling's solutions or copper sulfate tablets. For glucose determination in urine, a glucose oxidase test is recommended.

During cefixime administration, a false-positive direct Coombs' test may occur. Therefore, it should be noted that a positive Coombs' test result may be due to the use of this medicinal product.

Special precautions.

Encephalopathy.

When using beta-lactam antibiotics, including cefixime, the risk of developing encephalopathy (which may manifest as seizures, confusion, impaired consciousness, and motor disturbances) increases, particularly in cases of overdose or in patients with pre-existing renal impairment.

Severe skin reactions.

Serious skin adverse reactions, such as toxic epidermal necrolysis, Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms (DRESS syndrome), and acute generalized exanthematous pustulosis (AGEP), have been observed in some patients receiving cefixime. Patients should be informed about the signs and symptoms of serious skin manifestations and should be closely monitored. Treatment should be discontinued at the first sign of a skin rash, mucosal lesions, or any other signs of skin hypersensitivity. Appropriate treatment and/or preventive measures should be initiated in cases of serious skin adverse reactions.

Hypersensitivity reactions.

Prior to initiating cefixime therapy, it is essential to determine whether the patient has a history of hypersensitivity reactions to cephalosporins, penicillins, or other drugs. The drug should be administered with caution in patients with known allergies, especially to penicillins, cephalosporins, or other medications. Severe reactions (including anaphylactic reactions and cross-allergic reactions) have been reported in some patients, and in rare cases, fatal outcomes have occurred (see section "Adverse reactions"). If an allergic reaction to cefixime occurs, the drug should be discontinued immediately and appropriate treatment initiated.

Hemolytic anemia.

Cases of hemolytic anemia, including severe cases with fatal outcomes, have been reported following the use of cephalosporins. Recurrent episodes of hemolytic anemia have also been documented after cephalosporin administration in patients who previously experienced hemolytic anemia following initial exposure to cephalosporins, including cefixime.

Acute renal failure.

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 interventions initiated.

Renal function impairment.

Cefixime should be used with caution in patients with significantly impaired renal function (see section "Dosage and administration", "Dosage in renal impairment").

Use in pediatrics.

The safety of cefixime in preterm infants or newborns has not been established.

Pseudomembranous colitis/overgrowth of resistant microorganisms.

Caution is advised 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 large intestine and may lead to rapid overgrowth of Clostridia. The toxin produced by Clostridium difficile is the main cause of antibiotic-associated diarrhea. Prolonged use of the drug may disrupt the normal intestinal flora, potentially leading to overgrowth of Candida albicans and resulting in oral mucosal candidiasis. Severe diarrhea and pseudomembranous colitis may also develop. Symptoms of pseudomembranous colitis may appear during or after discontinuation of antibiotic therapy.

In mild cases of pseudomembranous colitis caused by antibiotic use, discontinuation of the drug may be sufficient. If colitis symptoms do not resolve after discontinuation, oral vancomycin should be administered, as it is the antibiotic of choice for pseudomembranous colitis. In cases of moderate to severe colitis, electrolyte and protein solutions should be added to the treatment regimen. Concomitant use of drugs that reduce intestinal peristalsis should be avoided. Other causes of colitis must be ruled out.

Effect on serological test results.

A positive direct Coombs' test and false-positive urine glucose tests may occur during treatment. If corresponding symptoms are present, cefixime therapy should be discontinued and appropriate investigations and treatment initiated.

Laboratory test findings.

Reversible changes in liver, kidney, and blood parameters (thrombocytopenia, leukopenia, and eosinophilia) may occur during treatment.

Alcohol.

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

Excipients.

The medicinal product contains lactose. Patients with known sugar intolerances should consult their physician before taking this medicinal product.

Use during pregnancy or breastfeeding.

Reproductive studies in animals receiving doses nearly 400 times higher than the human dose showed no effect on fertility or fetal abnormalities due to cefixime administration. In animals, 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 animals to antibiotic-induced changes in intestinal flora.

There are no data on the use of the drug during pregnancy. Cefixime crosses the placental barrier.

The drug should not be used during pregnancy or breastfeeding except when prescribed by a physician in cases of urgent medical need.

Ability to affect reaction speed when driving or operating machinery.

If adverse reactions such as encephalopathy (which may include seizures, confusion, impaired consciousness, and motor disturbances) occur, patients should avoid driving or operating machinery.

Method of administration and dosage.

The usual treatment course is 7 days; if necessary, up to 14 days. In the treatment of uncomplicated cystitis, the treatment course is 3 days.

Adults.

The recommended dose for adults is 200–400 mg per day, depending on the severity of infection, administered as a single dose or in two divided doses.

Elderly patients.

The drug should be administered at the recommended adult dose. Renal function should be monitored and the dose adjusted in case of severe renal impairment.

Children with body weight over 50 kg or aged 10 years and older.

Treatment should be conducted according to the recommended adult dose (200–400 mg per day depending on the severity of infection).

The safety and efficacy of cefixime have not been established in children under 6 months of age.

Dosing in renal impairment.

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

Children.

For children under 10 years of age, it is recommended to use the drug in another pharmaceutical form.

Overdose.

There is a risk of developing encephalopathy when using beta-lactam antibiotics, including cefixime, especially in cases of overdose or impaired renal function. Study data have shown that at doses up to 2 g per day, cefixime has a safety profile similar to that of recommended therapeutic doses.

Dialysis contributes only minimally to the elimination of cefixime from the body. There is no specific antidote. General supportive therapy is recommended.

Adverse reactions.

Adverse reactions caused by cefixime are mild and occur rarely.

Blood and lymphatic system disorders: eosinophilia, hyper-eosinophilia, agranulocytosis (isolated cases of coagulation disorders have been reported), leukopenia, neutropenia, granulocytopenia, hemolytic anemia, thrombocytopenia, thrombocytosis, hypoprothrombinemia (bleeding and bruising without apparent cause), thrombophlebitis, prolonged thrombin and prothrombin time, purpura.

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

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

Hepatic disorders: jaundice, hepatitis, cholestasis, scleral icterus, skin icterus.

Infections and infestations: pseudomembranous colitis, vaginitis, vaginal candidiasis.

Laboratory findings: increased serum levels of transaminases (AST, ALT) or alkaline phosphatase, bilirubin, urea, and creatinine.

Auditory disorders: hearing loss.

Nervous system disorders: headache, dizziness, dysphoria, hyperactivity, 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, altered consciousness, movement disorders) in patients, especially in cases of overdose and renal impairment (frequency unknown)**.

Respiratory system disorders: dyspnea.

Renal and urinary system disorders: acute renal failure, including tubulointerstitial nephritis as the main pathological condition (see section "Special instructions"), hematuria.

Immune system disorders: anaphylactic reactions, angioedema, serum sickness-like reactions.

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

General disorders: fever, arthralgia, facial swelling, genital pruritus, weakness, fatigue, increased sweating, mucosal inflammation.

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

**Cannot be estimated from the available data.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the drug. Healthcare professionals and patients, or their legal representatives, should report all suspected adverse reactions and lack of drug 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 in the original packaging. Keep out of reach of children.

Packaging.

10 tablets per blister pack, 1 blister pack per carton.

Prescription status.

Prescription only.

Manufacturer.

Sens Laboratories Pvt. Ltd.

Manufacturer's address and place of business.

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

Marketing Authorization Holder. Ananta Medikare Ltd.

Address of the Marketing Authorization Holder. Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.