CEDOM - 250

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEDOM - 250 (CEDOM - 250)

Composition:

Active substance: cefdinir;

250 mg of cefdinir in 5 ml of suspension;

Excipients: sucrose, xanthan gum, colloidal anhydrous silicon dioxide, sodium citrate, anhydrous citric acid, strawberry flavor, quinoline yellow (E 104).

Pharmaceutical form. Powder for oral suspension.

Main physicochemical properties:

for the dry powder: granular yellow powder with a characteristic odor; for the reconstituted suspension: light yellow suspension.

Pharmacotherapeutic group.

Antibacterials for systemic use. Third-generation cephalosporins.

ATC code J01D D15.

Pharmacological properties.

Pharmacodynamics.

Cefdinir is a third-generation cephalosporin with broad activity against enteric gram-negative bacteria. Cefdinir is stable in the presence of certain β-lactamase enzymes. As a result, many organisms resistant to penicillins and some cephalosporins remain susceptible to cefdinir. Cephalosporins act similarly to penicillins: they inhibit bacterial cell wall peptidoglycan synthesis by inhibiting the final transpeptidation step required for cross-linking. This effect is bactericidal.

Mechanism of action

Cefdinir is a β-lactam antibiotic, similar to penicillins, and is predominantly bactericidal. Cefdinir inhibits the third and final stage of bacterial cell wall synthesis, primarily by binding to penicillin-binding proteins (PBPs) located within the bacterial cell wall. PBPs are responsible for several steps in cell wall synthesis. Thus, the intrinsic activity of cefdinir, as with other cephalosporins and penicillins, against a specific organism depends on its ability to access and bind to the essential PBPs. Like all β-lactam antibiotics, cefdinir's ability to interfere with PBP-mediated cell wall synthesis ultimately leads to cell lysis. Lysis is mediated by autolytic enzymes of the bacterial cell wall, i.e., autolysins. Mechanism of resistance

Resistance to cefdinir primarily occurs through hydrolysis by certain β-lactamases, alteration of PBPs, and reduced permeability. Cefdinir is inactive against most strains of Enterobacter spp., Pseudomonas spp., Enterococcus spp., penicillin-resistant streptococci, and methicillin-resistant staphylococci. β-lactamase-negative, ampicillin-resistant (BLNAR) strains of H. influenzae are generally not susceptible to cefdinir.

Antimicrobial susceptibility testing for cefdinir

a Streptococci, other than S. pneumoniae, that are penicillin-susceptible (MIC 0.12 mcg/mL) can be considered susceptible to cefdinir.

b S. pneumoniae that are penicillin-susceptible (MIC 0.06 mcg/mL) can be considered susceptible to cefdinir. Isolates of S. pneumoniae tested against a 1 mcg oxacillin disk with oxacillin zone diameters of 20 mm are susceptible to penicillin and may be considered susceptible to cefdinir. Testing cefdinir against penicillin-intermediate or penicillin-resistant isolates is not recommended. There are no established interpretive criteria for cefdinir.

Antimicrobial Activity

Cefdinir has been shown to be active in vitro and during clinical infections against most strains of the following microorganisms.

Gram-Positive Bacteria

Staphylococcus aureus (methicillin-susceptible strains only)

Streptococcus pneumoniae (penicillin-susceptible strains only)

Streptococcus pyogenes

Gram-Negative Bacteria

Haemophilus influenzae

Haemophilus parainfluenzae

Moraxella catarrhalis

The following in vitro data are available, but their clinical significance is unknown.

Cefdinir has demonstrated in vitro minimum inhibitory concentrations (MICs) of 1 mcg/mL or less against (≥ 90%) strains of the following microorganisms; however, the safety and efficacy of cefdinir in treating clinical infections caused by these microorganisms have not been established in adequate and well-controlled clinical trials.

Gram-Positive Bacteria

Staphylococcus epidermidis (methicillin-susceptible strains only)

Streptococcus agalactiae

Viridans group streptococci

Gram-Negative Bacteria

Citrobacter koseri

Escherichia coli

Klebsiella pneumoniae

Proteus mirabilis

Pharmacokinetics

Cefdinir is administered orally. After entering systemic circulation, cefdinir is 60–70% bound to plasma proteins in both adults and children. Protein binding is independent of concentration. Distribution occurs in various tissues, including lungs, middle ear fluid, sinuses, skin bullae, and tonsils. There are no data on penetration of cefdinir into human cerebrospinal fluid. Cefdinir undergoes negligible metabolism, and its activity is primarily due to the parent drug. Elimination occurs primarily via renal excretion, with a mean plasma half-life of approximately 1.7 hours.

Absorption

Oral Bioavailability

Maximum plasma concentration of cefdinir is observed 2–4 hours after dosing. Plasma concentrations of cefdinir increase with increasing dose, but the increase in concentration is less than proportional over the dose range of 300 mg (7 mg/kg) to 600 mg (14 mg/kg). Following administration of the suspension to healthy adult volunteers, the bioavailability of cefdinir is 120% relative to capsules. The calculated absolute bioavailability of cefdinir suspension is 25%. The oral suspension of cefdinir 250 mg/5 mL has been shown to be bioequivalent to the 125 mg/5 mL dosage formulation in healthy adult volunteers under fasting conditions.

Effect of Food

In adults who received the 250 mg/5 mL oral suspension with a high-fat meal, the maximum concentration (Cmax) and area under the concentration–time curve (AUC) of cefdinir decreased by 44% and 33%, respectively. The magnitude of these reductions is not considered clinically significant, as safety and efficacy studies of the oral suspension in pediatric patients were conducted without regard to food intake. Therefore, cefdinir may be administered without regard to food.

Metabolism and Excretion

Cefdinir undergoes negligible metabolism. Activity is primarily due to the parent compound. Cefdinir is eliminated primarily by renal excretion, with a mean plasma elimination half-life (t½) of 1.7 (± 0.6) hours. In healthy volunteers with normal renal function, renal clearance is 2.0 (± 1.0) mL/min/kg, and peripheral clearance is 11.6 (± 6.0) mL/min/kg and 15.5 (± 5.4) mL/min/kg after 300 mg and 600 mg doses, respectively. The mean percentage of dose excreted unchanged in urine after 300 mg and 600 mg doses is 18.4% (± 6.4) and 11.6% (± 4.6), respectively. Renal clearance is reduced in patients with impaired renal function.

Because renal excretion is the primary route of elimination, dosage adjustment is recommended in patients with significant renal impairment or those undergoing hemodialysis.

Clinical characteristics.

Indications.

Mild to moderate infections caused by susceptible strains of the appropriate microorganisms:

• Community-acquired pneumonia caused by Haemophilus influenzae (including β-lactamase-producing strains), Haemophilus parainfluenzae (including β-lactamase-producing strains), Streptococcus pneumoniae (penicillin-susceptible strains only), and Moraxella catarrhalis (including β-lactamase-producing strains);
• Exacerbations of chronic bronchitis caused by Haemophilus influenzae (including β-lactamase-producing strains), Haemophilus parainfluenzae (including β-lactamase-producing strains), Streptococcus pneumoniae (penicillin-susceptible strains only), and Moraxella catarrhalis (including β-lactamase-producing strains);
• Acute sinusitis caused by Haemophilus influenzae (including β-lactamase-producing strains), Streptococcus pneumoniae (penicillin-susceptible strains only), and Moraxella catarrhalis (including β-lactamase-producing strains);
• Pharyngitis/tonsillitis caused by Streptococcus pyogenes;
• Uncomplicated skin and soft tissue infections caused by Staphylococcus aureus (including β-lactamase-producing strains) and Streptococcus pyogenes;
• Acute bacterial otitis media caused by Haemophilus influenzae (including β-lactamase-producing strains), Streptococcus pneumoniae (penicillin-susceptible strains only), and Moraxella catarrhalis (including β-lactamase-producing strains).

Contraindications.

The drug is contraindicated in patients with known hypersensitivity to cephalosporin antibiotics.

Interaction with other medicinal products and other forms of interactions.

Antacids (aluminum- or magnesium-containing)

Concomitant administration of 300 mg cefdinir and 30 mL of aluminum hydroxide and magnesium hydroxide suspension resulted in approximately a 40% reduction in the rate (Cmax) and extent (AUC) of absorption. Time to reach Cmax was also prolonged by 1 hour. Antacids do not have a significant effect on cefdinir pharmacokinetics if administered 2 hours before or 2 hours after cefdinir. If antacid use during cefdinir therapy is necessary, the drug should be taken at least 2 hours before or 2 hours after antacid administration.

Probenecid

As with other β-lactam antibiotics, probenecid inhibits renal excretion of cefdinir, resulting in approximately a doubling of AUC, a 54% increase in Cmax, and a 50% prolongation of t½.

Iron supplements and iron-fortified foods

Concomitant administration of cefdinir with iron-containing medicinal products containing 60 mg of elemental iron (as FeSO4) or vitamin products containing 10 mg of elemental iron reduces cefdinir absorption by 80% and 31%, respectively. If iron supplementation is required during cefdinir therapy, cefdinir should be administered at least 2 hours before or 2 hours after iron-containing medicinal products. The effect of foods high in elemental iron (primarily iron-fortified breakfast cereals) on cefdinir absorption has not been studied. Iron-fortified infant formula does not significantly affect cefdinir pharmacokinetics. Based on this, cefdinir oral suspension may be administered simultaneously with iron-fortified infant formula.

Cases of reddish discoloration of stools have been reported in patients receiving the drug. In many cases, these patients were concurrently receiving iron-fortified products. The reddish color is due to the formation of a complex between cefdinir or its degradation products and iron, which is not absorbed in the gastrointestinal tract.

Warfarin

Concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the international normalized ratio (INR), thereby increasing the risk of bleeding. The mechanism involves inhibition of vitamin K synthesis due to changes in gut flora; however, the presence of concurrent infection is also a potential risk factor for increased INR. Patients should be monitored for signs and symptoms of bleeding. In addition, intensified INR monitoring may be required, especially at the beginning and after discontinuation of antibiotic therapy.

Special precautions.

Warning

Prior to initiating therapy with cefdinir, a thorough evaluation should be conducted to determine whether the patient has had previous hypersensitivity reactions to cefdinir, other cephalosporins, penicillins, or other drugs. Caution should be exercised when prescribing cefdinir to patients with penicillin sensitivity, as cross-hypersensitivity among β-lactam antibiotics has been demonstrated and may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to cefdinir occurs, the drug should be discontinued. In the event of a severe hypersensitivity reaction, administration of epinephrine and other emergency measures may be required, including oxygen supply, intravenous fluids, intravenous antihistamines, corticosteroids, pressor amines, and ensuring airway patency, as clinically indicated. With the use of nearly all antibacterial agents, including cefdinir, Clostridium difficile-associated diarrhea (CDAD) has been reported, with severity ranging from mild diarrhea to fatal colitis. Antibacterial agents alter the normal flora of the colon, leading to overgrowth of C. difficile strains. C. difficile produces toxins A and B, which contribute to the development of pseudomembranous colitis. Toxigenic strains of C. difficile are associated with increased morbidity and mortality, as these infections may be refractory to antimicrobial therapy and may require colectomy. Patients who develop diarrhea following antibiotic use should be evaluated for pseudomembranous colitis. A careful medical history is essential, as symptoms of pseudomembranous colitis may appear up to 2 months after antibiotic administration. If pseudomembranous colitis is suspected or confirmed, antibiotics not directed against C. difficile should be discontinued. Depending on the clinical condition, management may include restoration of fluid and electrolyte balance, administration of electrolyte and amino acid solutions, antibiotic therapy directed against Clostridium difficile, or surgical intervention.

Safety measures

General use of cefdinir in the absence of confirmed or strongly suspected bacterial infection, or without a valid indication for prophylactic use, is of questionable benefit to the patient and increases the risk of developing antibiotic-resistant bacteria.

As with other broad-spectrum antibiotics, prolonged treatment with cefdinir may result in overgrowth of organisms resistant to the drug. Close monitoring of the patient is required. If superinfection develops during therapy, appropriate alternative treatment should be instituted. Cefdinir, like other broad-spectrum antimicrobial agents (antibiotics), should be used with caution in patients with a history of colitis. In patients with transient or persistent renal impairment (creatinine clearance < 30 mL/min), the total daily dose of cefdinir should be reduced, as administration of the recommended doses may lead to significantly increased plasma concentrations and prolonged elimination half-life of cefdinir.

False-positive urine glucose reactions have been observed in patients receiving cephalosporins such as cefdinir. Diabetic patients who monitor their urine glucose during cefdinir therapy should use glucose tests based on glucose oxidase enzymatic reactions.

Important information about excipients

The medicinal product Cedem-250 contains sucrose. If intolerance to certain sugars has been diagnosed, consultation with a physician is necessary before taking this medicinal product.

Use during pregnancy or breastfeeding

The medicinal product is intended for use in children. Adequate and well-controlled studies on the use of cefdinir in pregnant women have not been conducted. Cefdinir was not detected in human breast milk after a single 600 mg dose.

Ability to influence reaction rate when driving or operating machinery

The medicinal product is intended for use in children. Cefdinir may cause adverse reactions that affect concentration and reaction speed.

Dosage and Administration

Route of administration: Oral.

Dosing

The recommended dosing regimen and duration of treatment for infections in children are described in the table below. The total daily dose for all infections is 14 mg/kg, up to a maximum dose of 600 mg per day. Administration of the medicinal product once daily for 10 days is as effective as administration twice daily. However, once-daily dosing has not been studied in skin infections; therefore, cefdinir as oral suspension should be administered twice daily for these infections. The suspension may be taken with or without food.

Children (under 12 years of age)

Approximate dosing regimen for cefdinir in children

* The dose is determined individually by a physician depending on the patient's age and body weight. For all patients aged from 6 months to 12 years, the single dose of the medicinal product is 7 mg/kg of body weight or 0.14 mL of suspension per 1 kg of body weight.

** For children with body weight ≥ 43 kg, the medicinal product is administered at the maximum daily dose of 600 mg.

Patients with renal function impairment

The recommended dose of cefdinir for patients with creatinine clearance (CLcr) < 30 mL/min is 300 mg once daily; for children – 7 mg/kg once daily (up to 300 mg daily).

Creatinine clearance is difficult to measure in an outpatient setting. However, the following formula may be used to estimate CLcr in adult patients. Plasma creatinine levels should reflect a steady-state renal function.

(ml/min) =

The following formula may be used to determine CLcr in children:

where K = 0.55 for children aged 1 year and older, and 0.45 for infants (under 1 year of age).

In both cases, CLcr is calculated in ml/min/1.73 m², body length or height is expressed in centimeters, and serum creatinine is expressed in mg/dL.

Patients on hemodialysis

Cefdinir is removed from the body by hemodialysis.

For patients undergoing chronic hemodialysis, the recommended initial dosage regimen is 300 mg or 7 mg/kg every other day. After each hemodialysis session, administer 300 mg (or 7 mg/kg). Subsequent doses (300 mg or 7 mg/kg) should be given every other day.

Reconstitution instructions for cefdinir oral suspension

Before reconstitution, shake the bottle to loosen the powder. Add boiled, cooled water up to the mark on the bottle and shake well. Add additional boiled, cooled water if necessary to reach the mark (the total volume of water to be added to the mark on the bottle is 38 ml). The reconstituted suspension should be shaken well before each administration.

Children

The drug is indicated for children aged 6 months to 12 years. Safety and efficacy of the drug in children under 6 months of age have not been established.

Overdose

Symptoms. Information on cefdinir overdose in humans is not available. Toxic signs and symptoms following overdose with other β-lactam antibiotics included nausea, vomiting, epigastric distress, diarrhea, and seizures.

Treatment. Cefdinir is removed from the body by hemodialysis. This information should be considered in cases of severe intoxication due to overdose, especially in patients with impaired renal function.

Adverse reactions.

Adverse reactions associated with the use of cefdinir in studies involving adult patients, adolescents, and children:

The above-mentioned adverse reactions were observed during clinical trials and/or the post-marketing period.

The following adverse reactions and laboratory test abnormalities, regardless of their relationship to cefdinir use, have been reported during the long-term post-marketing period: Stevens–Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, erythema multiforme, erythema nodosum, diarrhea with blood, hemorrhagic colitis, pseudomembranous colitis, pancytopenia, granulocytopenia, leukopenia, thrombocytopenia, idiopathic thrombocytopenic purpura, hemolytic anemia, bleeding tendency, coagulation disorders, disseminated intravascular coagulation syndrome, upper gastrointestinal tract bleeding, loss of consciousness, allergic vasculitis, hypertensive disease, involuntary movements.

The following adverse reactions and laboratory abnormalities have been reported, which are generally characteristic of cephalosporin antibiotics:

allergic reactions, anaphylaxis, Stevens–Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, renal function impairment, toxic nephropathy, hepatic dysfunction including cholestasis, aplastic anemia, hemolytic disease, pancytopenia, and agranulocytosis. Symptoms of pseudomembranous colitis may occur during or after antibiotic therapy.

Seizures have been reported with some cephalosporins, particularly in patients with impaired renal function for whom dose adjustment was not performed. If seizures occur during therapy, the drug should be discontinued. Anticonvulsant therapy may be indicated if clinically necessary.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: 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.

The prepared suspension should be stored for no more than 10 days at a temperature not exceeding 25 °C.

Packaging.

One vial containing powder for the preparation of 60 mL of suspension, supplied with an oral dosing syringe, in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Sens Laboratory Pvt. Ltd.

Manufacturer's address and location of manufacturing site.

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