Cedoxim

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEDOXIM® (CEDOXIM®)

Composition:

Active substance: cefpodoxime;

5 ml of suspension contains 40 mg of cefpodoxime proxetil, calculated as cefpodoxime;

Excipients: lactose monohydrate, corn starch, sodium croscarmellose, iron oxide yellow (E 172), low-substituted hydroxypropyl cellulose, dispersible cellulose*, colloidal anhydrous silicon dioxide, anhydrous citric acid, sodium citrate, sodium benzoate (E 211), flavoring additive Banana dry flavor 501392TDI0991**, sucrose.

* Dispersible cellulose: sodium carboxymethylcellulose – microcrystalline cellulose.

** Flavoring additive Banana dry flavor 501392TDI0991: spherical sugar, maltodextrin, natural banana flavoring, medium-chain triglycerides, silicon dioxide, lecithin.

Pharmaceutical form. Powder for oral suspension.

Main physicochemical properties:

For the dry powder: granular, almost white-colored powder.

For the prepared suspension: almost white-colored suspension with a banana odor.

Pharmacotherapeutic group.

Antibacterial agents for systemic use. Other β-lactam antibiotics. Third-generation cephalosporins. ATC code J01D D13.

Pharmacological Properties

Pharmacodynamics

Cedoxime® is a third-generation β-lactam antibiotic for oral administration. Its bactericidal effect is due to inhibition of bacterial cell wall synthesis in microorganisms. The drug is active against many Gram-positive, Gram-negative, aerobic, and anaerobic microorganisms.

The spectrum of activity of cefpodoxime includes the following microorganisms:

Susceptible Gram-positive bacteria – Streptococcus pneumoniae, group A streptococci (S. pyogenes), group B (S. agalactiae), groups C, F, and G, as well as S. mitis, S. sanguis, S. salivarius, and Corynebacterium diphtheriae;

Susceptible Gram-negative bacteria – Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella (Branhamella) catarrhalis (both β-lactamase-producing and non-producing strains), Neisseria meningitidis, Neisseria gonorrhoeae, Escherichia coli, Klebsiella spp. (K. pneumoniae; K. oxytoca), Proteus mirabilis;

Moderately susceptible bacteria – methicillin-susceptible staphylococci, both penicillinase-producing and non-producing strains (S. aureus and S. epidermidis).

Bacteria resistant to cefpodoxime, as well as to other cephalosporins, include: enterococci, methicillin-resistant staphylococci (S. aureus and S. epidermidis), Staphylococcus saprophyticus, Pseudomonas aeruginosa and Pseudomonas spp., Clostridium difficile, Bacteroides fragilis.

Pharmacokinetics

The active ingredient of the drug is absorbed in the small intestine and hydrolyzed to the active metabolite, cefpodoxime. Maximum plasma concentrations are achieved within 2–4 hours after administration of a single dose. Cefpodoxime binds to plasma proteins (mainly albumins) in a non-saturable manner. The minimum inhibitory concentration (MIC) of cefpodoxime against most pathogens is observed in lung parenchyma, bronchial mucosa, pleural fluid, tonsils, interstitial fluid, and prostatic gland secretion.

It penetrates well into kidney tissues. Within 12 hours after administration of a single dose, MIC90 is achieved against most pathogens causing kidney and urinary tract infections. The drug is primarily excreted in urine, with a half-life of approximately 2.4 hours.

Clinical characteristics.

Indications.

Infections caused by cefpodoxime-susceptible microorganisms:

• Ear, nose, and throat (ENT) organs (including acute otitis media, sinusitis, tonsillitis, pharyngitis); the drug should be prescribed for the treatment of chronic or recurrent infections, as well as in cases of known or suspected resistance of the pathogen to commonly used antibiotics;
• respiratory tract (including pneumonia, acute bronchitis or bronchiolitis complicated by bacterial superinfection);
• uncomplicated infections of the upper and lower urinary tract (including acute pyelonephritis and cystitis);
• skin and soft tissues (abscesses, cellulitis, infected wounds, furuncles, folliculitis, paronychia, carbuncles, and ulcers).

Contraindications.

Hypersensitivity to cephalosporin drugs, penicillins, or to any component of the drug. Hereditary fructose intolerance or sucrase-isomaltase deficiency.

Interaction with other medicinal products and other types of interactions.

Concomitant administration of high doses of antacid agents (sodium bicarbonate and aluminum hydroxide) or histamine H2-receptor blockers reduces the extent of absorption by 27–32% and peak concentration by 24–42%. Oral anticholinesterase agents increase the time to peak concentration by 47%, but do not affect the extent of absorption. If co-administration with ranitidine is necessary, the drug should be taken 2–3 hours after administration of ranitidine.

Cephalosporins may potentially enhance the anticoagulant effect of coumarins and reduce the efficacy of estrogens.

The bioavailability of cefpodoxime increases when administered with food.

A false-positive reaction may occur in tests for glucosuria using copper-reduction methods (Benedict's or Fehling's), however, this does not affect the determination of glucose in urine by enzymatic methods.

Concomitant use of the drug with loop diuretics may increase nephrotoxicity. Careful monitoring of renal function is recommended if Cedoxim**®** is administered simultaneously with drugs exhibiting nephrotoxic effects. Plasma levels of cefpodoxime increase when the drug is administered with probenecid.

Special precautions for use.

Hypersensitivity reactions.

Due to possible cross-hypersensitivity, it is essential to determine prior to initiating therapy whether the patient has a history of severe hypersensitivity reactions to cephalosporin or penicillin antibiotics. If an allergic reaction to cefpodoxime occurs, the drug should be discontinued immediately. Allergic reactions (particularly anaphylaxis) associated with the use of β-lactam antibiotics may be severe and, in rare cases, fatal (see section "Adverse reactions").

Severe cutaneous adverse reactions (SCARs)

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), which may be life-threatening or result in death, have been reported with "unknown" frequency in association with cefpodoxime therapy.

Patients should be informed about the signs and symptoms and closely monitored for skin reactions.

If signs or symptoms suggestive of these reactions occur, cefpodoxime should be discontinued immediately, and alternative treatment options should be considered.

If a serious reaction such as SJS, TEN, DRESS, or AGEP develops during cefpodoxime therapy, re-administration of cefpodoxime is absolutely contraindicated.

Antibacterial spectrum of activity.

Cefpodoxime is not the drug of choice for the treatment of staphylococcal pneumonia and should not be used in the treatment of atypical pneumonia caused by Legionella, Mycoplasma, or Chlamydia species.

Effect on renal function.

Dosage regimen should be adjusted in patients with renal impairment according to creatinine clearance values (recommended doses are shown in the table below). Concomitant use of Cedoxim**®** with aminoglycosides or potent diuretics may lead to deterioration of renal function. Renal function parameters should be monitored during treatment.

Colitis/overgrowth of non-susceptible microorganisms.

Gastrointestinal adverse reactions (e.g., vomiting, nausea, abdominal pain) may occur. Antibiotics should always be prescribed with caution in patients with gastrointestinal disorders, particularly colitis.

Treatment with cefpodoxime and other broad-spectrum antibiotics may disrupt the normal intestinal flora balance, potentially leading to diarrhea or colitis, including Clostridium difficile-associated pseudomembranous colitis. These adverse reactions, which are more likely in patients receiving high doses of cefpodoxime for prolonged periods, should be considered potentially serious.

Testing for Clostridium difficile should be performed. If colitis is suspected, the drug should be discontinued immediately. Diagnosis should be confirmed by sigmoidoscopy and/or rectoscopy, and, if clinically indicated, alternative antibiotic therapy (e.g., vancomycin) should be initiated. Medications that cause fecal retention should be avoided.

Prolonged use of cefpodoxime may lead to overgrowth of non-susceptible microorganisms, including disruption of normal intestinal flora, which may result in overgrowth of Candida and development of oral mucosal candidiasis (see section "Adverse reactions"). If superinfection occurs, the patient's condition should be evaluated and appropriate treatment initiated.

Effect on blood system.

With the use of β-lactam antibiotics, neutropenia and agranulocytosis may develop, particularly during prolonged therapy. If neutropenia occurs, treatment with Cedoxim**®** should be discontinued.

Effect on serological test results.

Cefpodoxime may cause false-positive results in the Coombs test. Decreased hemoglobin levels may also occur; hemolytic anemia is very rare.

Use during pregnancy or breastfeeding.

The drug is intended for use in children.

Ability to affect reaction rate while driving or operating machinery.

The drug is intended for use in children.

Dosage and Administration.

Cedoxime® suspension is intended for use in pediatric practice. The prepared suspension should be taken orally during meals to enhance absorption.

For children aged 5 months to 12 years, the recommended dose is 8 mg/kg body weight per day (maximum daily dose – 400 mg), administered in two divided doses every 12 hours (maximum single dose – 200 mg). The duration of treatment depends on the severity of the disease and is determined individually.

Hepatic impairment.

Dosage adjustment is not required for children with hepatic insufficiency.

Renal impairment.

Dosage adjustment of Cedoxime® is not necessary if creatinine clearance is ≥40 mL/min.

If creatinine clearance is below 40 mL/min, pharmacokinetic studies indicate an increased elimination half-life and maximum plasma concentration; therefore, the dose of the drug should be adjusted accordingly.

Table 1

For patients undergoing hemodialysis, a single dose calculated according to body weight should be administered after each dialysis session.

Instructions for the preparation of the suspension

To prepare the suspension, turn the bottle upside down and shake vigorously to loosen the powder. Add boiled water cooled to room temperature in two portions up to the line on the bottle (mark), shaking vigorously each time, until a homogeneous suspension is formed. The prepared suspension may be taken no earlier than 5 minutes after preparation. The resulting suspension should be stored for 10 days at 2–8 °C in the refrigerator. Before each administration, the ready-to-use suspension must be shaken well.

Children.

The drug is indicated for children aged 5 months to 12 years.

Overdose.

Symptoms: nausea, vomiting, abdominal pain, diarrhea. In cases of overdose, especially in patients with renal insufficiency, encephalopathy may occur. Episodes of encephalopathy are usually reversible with low plasma levels of cefpodoxime.

Treatment. Hemodialysis, peritoneal dialysis. Symptomatic therapy.

Adverse Reactions

Blood system disorders: eosinophilia; leukopenia, hemorrhage, neutropenia, thrombocytopenia, thrombocytosis, positive Coombs test, agranulocytosis, serum sickness, decreased hematocrit, decreased hemoglobin concentration, hemolytic anemia, prolonged thrombin and prothrombin time, leukocytosis, lymphopenia, lymphocytosis.

Immune system disorders: hypersensitivity, anaphylactic reactions, angioneurotic edema.

Metabolism and nutrition disorders: dehydration, gout, peripheral edema, weight gain.

Musculoskeletal system disorders: myalgia, arthralgia.

Nervous system disorders: headache, dizziness, unsteadiness, cephalalgia, weakness, insomnia, somnolence, sleep disturbances, neurosis, irritability, nervousness, anxiety, unusual dreams, visual disturbances, confusion, night terrors, paresthesia.

Respiratory system disorders: asthma, bronchitis, cough, epistaxis, sneezing, rhinitis, wheezing, dyspnea, bronchospasm, sinusitis, pleural effusion, pneumonia.

Gastrointestinal disorders: abdominal pain, nausea; diarrhea, thirst, tenesmus, bloating, vomiting, dyspepsia, dry mouth, decreased appetite, sensation of pressure/fullness in stomach, constipation, candidal stomatitis, toothache, anorexia, belching, gastritis, mouth ulcers, pseudomembranous colitis.

Hepatobiliary disorders: cholestatic liver injury, increased levels of liver function tests (AST, ALT), alkaline phosphatase, and bilirubin.

Skin and subcutaneous tissue disorders: rash, erythema, pruritus, urticaria, increased sweating, maculopapular rash, fungal dermatitis, desquamation, dry skin, alopecia, vesicular rash, sunburn erythema, purpura, bullous reactions (including Stevens-Johnson syndrome), toxic epidermal necrolysis, erythema multiforme, acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS).

Renal and urinary system disorders: hematuria, urinary tract infections, metrorrhagia, dysuria, frequent urination, nocturia, genital infections, proteinuria, vaginal pain, vaginal candidiasis.

In isolated cases, renal function impairment has been observed.

Cardiovascular system disorders: congestive heart failure, tachycardia, vasodilation, hematoma, migraine, arterial hypertension or hypotension.

Eye disorders: eye irritation.

Ear and labyrinth disorders: tinnitus, vertigo.

General disorders: discomfort, increased fatigue, asthenia, chills, drug fever, chest pain (pain may radiate to the back), fever, generalized pain, localized swelling, localized pain, taste disturbances, abscess, allergic reaction, facial swelling, candidiasis, bacterial infections, parasitic infections.

Biochemical findings: hyper- or hypoglycemia, hypoalbuminemia, hypoproteinemia, hyperkalemia, hyponatremia.

Laboratory abnormalities: increased blood urea and creatinine levels.

Shelf life: 2 years.

Storage conditions:

Store at temperatures not exceeding 25°C in the original packaging.

Keep out of reach of children.

Packaging:

Powder in a 100 ml bottle; 1 bottle per cardboard package, supplied with a graduated measuring spoon.

Prescription status: Prescription only.

Manufacturer:

Aurobindo Pharma Ltd. Unit VI, Block D.

Manufacturer's address:

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

Marketing Authorization Holder:

Abhil Formulations Pvt. Ltd.