3-dinir

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT 3-DINIR (3-DINIR)

Composition:

Active substance: cefdinir;

5 ml of suspension contain cefdinir 250 mg;

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: yellow granular powder with a characteristic odor;

for the reconstituted suspension: light yellow suspension.

Pharmacotherapeutic group.

Antibacterial agent for systemic use. Third-generation cephalosporins.

ATC code J01D D15.

Pharmacological properties.

Pharmacodynamics.

Cefdinir is a semi-synthetic, broad-spectrum, oral third-generation cephalosporin antibiotic.

Mechanism of action

Like other cephalosporin antibiotics, cefdinir exerts a bactericidal effect against susceptible microorganisms by inhibiting cell wall synthesis. It is resistant to degradation by many beta-lactamases. As a result, many microorganisms resistant to penicillins and some cephalosporins remain susceptible to cefdinir.

Mechanism of resistance

Resistance to cefdinir primarily occurs through hydrolysis by certain β-lactamases, alterations in penicillin-binding proteins (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 strains of H. influenzae are generally non-susceptible to cefdinir.

Interpretive criteria for cefdinir susceptibility testing

Microorganismsa	MIC (μg/mL)			Zone diameter (mm)
	Susceptible	Intermediate	Resistant	Susceptible	Intermediate	Resistant
Haemophilus influenzae	≤1	--	--	≥20	--	--
Haemophilus parainfluenzae	≤1	--	--	≥20	--	--
Moraxella catarrhalis	≤1	2	≥4	≥20	17–19	≤16
Streptococcus pneumoniaeb	≤0.5	1	≥2	--	--	--
Streptococcus pyogenes	≤1	2	≥4	≥20	17–19	≤16

a Streptococci, excluding S. pneumoniae , susceptible to penicillin (MIC ≤ 0.12 mcg/mL), can be considered susceptible to cefdinir.

b S. pneumoniae susceptible to penicillin (MIC ≤ 0.06 mcg/mL) can be considered susceptible to cefdinir. Isolates of S. pneumoniae tested with a 1 mcg oxacillin disk showing oxacillin zone diameters ≥20 mm are susceptible to penicillin and may be considered susceptible to cefdinir. Testing of cefdinir activity against isolates that are intermediate or resistant to penicillin 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 (see section "Indications").

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 demonstrates in vitro minimum inhibitory concentrations (MICs) of 1 mcg/mL or less against ≥90% of the 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

Streptococcus Viridans group

Gram-Negative Bacteria

Citrobacter koseri

Escherichia coli

Klebsiella pneumoniae

Proteus mirabilis

Pharmacokinetics.

Absorption.

Oral Bioavailability. After oral administration, the time to reach maximum plasma concentration of cefdinir ranges from 2 to 4 hours. Plasma concentrations of cefdinir increase with increasing dose, although the increase becomes less than proportional in the dose range from 300 mg (7 mg/kg) to 600 mg (14 mg/kg). Following administration of the suspension to healthy adults, the bioavailability of cefdinir is 120% relative to capsules. The calculated bioavailability of cefdinir capsules is 21% after a 300 mg dose and 16% after a 600 mg dose. The calculated absolute bioavailability of cefdinir suspension is 25%. The 250 mg/5 mL oral suspension of cefdinir has been shown to be bioequivalent to the 125 mg/5 mL dosing in healthy adults under fasting conditions.

Effect of Food. In adults who received the 250 mg/5 mL oral suspension with a high-fat meal, the Cmax and AUC of cefdinir were reduced by 44% and 33%, respectively. The magnitude of these reductions is unlikely to be 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 regardless of food intake.

Distribution.

Cefdinir is 60–70% bound to plasma proteins in both adults and children; protein binding is independent of cefdinir concentration.

Distribution occurs in various tissues, including lungs, middle ear fluid, sinuses, skin blisters, and tonsils. Data on penetration of cefdinir into cerebrospinal fluid are not available.

Metabolism and Excretion.

Cefdinir undergoes no significant metabolism. Activity is primarily due to the unchanged compound. Cefdinir is eliminated mainly by renal excretion, with a mean elimination half-life (T1/2) of 1.7 (±0.6) hours.

In healthy volunteers (with normal renal function), the renal clearance of cefdinir is 2.0 (±1.0) mL/min/kg, and the apparent oral clearance is 11.6 (±6.0) and 15.5 (±5.4) mL/min/kg after administration of 300 mg and 600 mg cefdinir, respectively. The mean percentage of the dose excreted unchanged in urine after 300 mg and 600 mg doses is 18.4% (±6.4) and 11.6% (±4.6) of the administered dose, respectively. Cefdinir clearance is reduced in patients with impaired renal function.

Since renal excretion is the primary route of elimination of cefdinir, dosage should be appropriately adjusted in patients with severe renal impairment and in patients undergoing hemodialysis.

Clinical characteristics.

Indications.

To reduce the development of drug-resistant bacteria, the medicinal product should be used only for treatment or prevention of infections caused by susceptible bacteria. If culture and susceptibility data are available, they should be taken into account when selecting or modifying antibacterial therapy. In the absence of such data, empirical therapy should be guided by local epidemiological data and local patterns of susceptibility.

Mild to moderate infections in children 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 (only penicillin-susceptible strains);
• Moraxella catarrhalis (including β-lactamase-producing strains).

Acute exacerbation of chronic bronchitis caused by:

• Haemophilus influenzae (including β-lactamase-producing strains);
• Haemophilus parainfluenzae (including β-lactamase-producing strains);
• Streptococcus pneumoniae (only penicillin-susceptible strains);
• Moraxella catarrhalis (including β-lactamase-producing strains).

Acute sinusitis caused by:

• Haemophilus influenzae (including β-lactamase-producing strains);
• Streptococcus pneumoniae (only penicillin-susceptible strains);
• 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);
• Streptococcus pyogenes.

Acute bacterial otitis media caused by:

• Haemophilus influenzae (including β-lactamase-producing strains);
• Streptococcus pneumoniae (only penicillin-susceptible strains);
• Moraxella catarrhalis (including β-lactamase-producing strains).

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

Antacids (containing aluminium or magnesium)

Concomitant administration of 300 mg cefdinir with 30 mL of aluminium hydroxide and magnesium hydroxide suspension resulted in approximately 40% reduction in absorption rate, and the time to reach Cmax was prolonged by 1 hour. Antacids do not significantly affect the pharmacokinetics of cefdinir if administered 2 hours before or 2 hours after cefdinir. If antacids must be used during cefdinir therapy, cefdinir 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 twofold increase in AUC, a 54% increase in maximum plasma concentration, and a 50% prolongation of elimination half-life (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 preparations containing 10 mg of elemental iron reduces cefdinir absorption by 80% and 31%, respectively. If iron supplementation is necessary during cefdinir therapy, cefdinir should be administered at least 2 hours before or 2 hours after the iron-containing product. The effect of foods high in elemental iron (primarily iron-fortified breakfast cereals) on cefdinir absorption has not been studied.

Iron-fortified infant formula (2.2 mg elemental iron) does not significantly affect the pharmacokinetics of cefdinir. Therefore, cefdinir oral suspension may be administered simultaneously with iron-fortified infant formula.

Reddish discoloration of stools has been reported in patients receiving cefdinir. In many cases, these patients were concurrently receiving iron-fortified products. The reddish color is due to the formation of a non-absorbed complex of cefdinir or its degradation products with iron in the gastrointestinal tract.

Interaction of the medicinal product with laboratory tests

False-positive ketone tests in urine may occur with nitroprusside-based tests, but not with nitroferricyanide. Cefdinir may cause false-positive results in urine glucose tests using Clinitest®, Benedict's solution, or Fehling's reagent. Enzymatic glucose oxidase-based tests for glucose in urine (e.g., Clinistix® or Tes-Tape®) are recommended. Cephalosporin use may lead to a false-positive Coombs' test result.

Special precautions for use.

Safety measures

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

As with other broad-spectrum antibiotics, prolonged treatment with cefdinir may result in the emergence and overgrowth of microorganisms resistant to the drug. Close monitoring of the patient is required. If superinfection develops during therapy, appropriate alternative treatment should be initiated.

Effect on the immune system.

Prior to initiating cefdinir therapy, a careful evaluation should be performed 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 necessary, including oxygen, intravenous fluids, intravenous antihistamines, corticosteroids, pressor amines, and maintenance of airway patency, as clinically indicated.

Effect on the gastrointestinal tract.

Diarrhea associated with Clostridium difficile has been reported with nearly all antibacterial agents, including cefdinir, with severity ranging from mild diarrhea to fatal colitis. Antibacterial therapy alters 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. Toxin-producing strains of C. difficile are associated with increased morbidity and mortality, as these infections may be refractory to antimicrobial treatment and may require colectomy. Patients who develop diarrhea following antibiotic use should be evaluated for pseudomembranous colitis. Careful history taking is essential, as symptoms of pseudomembranous colitis have been reported to occur up to two months after administration of antibacterial agents. In case of suspected or confirmed pseudomembranous colitis, 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, antimicrobial therapy directed against Clostridium difficile, or surgical intervention.

Use in patients with a history of colitis.

Cefdinir, like other broad-spectrum antimicrobial agents (antibiotics), should be administered with caution in patients with a history of colitis.

Use in patients with renal impairment.

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 a significant increase in plasma concentrations and elimination half-life of cefdinir.

Important information about certain excipients.

The medicinal product contains sucrose. This should be taken into account in patients with diabetes mellitus. Medical consultation is required.

Use during pregnancy or breastfeeding.

The medicinal product is intended for use in children.

Pregnancy. Adequate and well-controlled studies of cefdinir use in pregnant women have not been conducted.

Breastfeeding period. Cefdinir was not detected in breast milk after a single 600 mg dose.

Ability to affect reaction speed while driving or operating machinery.

Experience with cefdinir has not revealed any adverse effect on the ability to drive vehicles or operate machinery.

Method of administration and dosage.

Dosing

The recommended dosing regimen and duration of treatment for infections in children are described in the table below; the total daily dose for treatment of all infections is 14 mg/kg, up to a maximum dose of 600 mg per day. Administration once daily for 10 days is as effective as administration twice daily. Once-daily dosing has not been studied in skin infections; therefore, cefdinir oral suspension should be taken twice daily for these infections. The suspension may be taken regardless of meals.

Children (aged 6 months to 12 years)

Infection type	Dosage	Duration of treatment
Acute bacterial otitis media	7 mg/kg every 12 hours or 14 mg/kg once every 24 hours	5–10 days 10 days
Acute sinusitis	7 mg/kg every 12 hours or 14 mg/kg once every 24 hours	10 days 10 days
Pharyngitis/tonsillitis	7 mg/kg every 12 hours or 14 mg/kg once every 24 hours	5–10 days 10 days
Uncomplicated skin and soft tissue infections	7 mg/kg every 12 hours	10 days

Approximate dosing schedule for cefdinir oral suspension for children*

Body weight	Every 12 hours	Every 24 hours	Body weight	Every 12 hours	Every 24 hours
7–8 kg	1 mL	2 mL	25–26 kg	3.5 mL	7 mL
9–10 kg	1.25 mL	2.5 mL	27–28 kg	3.75 mL	7.5 mL
11–12 kg	1.5 mL	3 mL	29–30 kg	4 mL	8 mL
13–14 kg	1.75 mL	3.5 mL	31–32 kg	4.25 mL	8.5 mL
15–16 kg	2 mL	4 mL	33–34 kg	4.75 mL	9.5 mL
17–18 kg	2.5 mL	5 mL	35–36 kg	5 mL	10 mL
19–20 kg	2.75 mL	5.5 mL	37–38 kg	5.25 mL	10.5 mL
21–22 kg	3 mL	6 mL	39–40 kg	5.5 mL	11 mL
23–24 kg	3.25 mL	6.5 mL	41–42 kg	5.75 mL	11.5 mL
			≥ 43**	6 mL	12 mL

* The dose is determined individually by a physician depending on the patient's age and body weight. For all patients aged 6 months to 12 years, the single dose of the drug 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 drug is administered at a maximum daily dose of 600 mg.

Patients with renal impairment

For pediatric patients with creatinine clearance < 30 mL/min/1.73 m², the dose of cefdinir should be 7 mg/kg (up to 300 mg) once daily.

Creatinine clearance is difficult to measure under outpatient conditions.

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

CLcr (mL/min/1.73 m2) =	___ K × height (cm) __________
	plasma creatinine (mg/dL)

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

Patients on hemodialysis

Cefdinir is removed from the body by hemodialysis.

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

Administration method

The medicinal product is intended for oral administration.

The suspension is prepared immediately before the first use.

Reconstitution of cefdinir powder for oral suspension

Final concentration	Final volume (ml)	Amount of water	Preparation of suspension
250 mg / 5 ml	60	38 ml	Tap the bottle to loosen the powder, then add water in two portions. Shake well after each addition of water.

Children.

The medicinal product is prescribed for children aged from 6 months (with body weight not less than 7 kg) to 12 years.

The safety and efficacy of the medicinal product in children under 6 months of age have not been studied.

Overdose.

Symptoms. There are no data on cefdinir overdose in humans. In acute toxicity studies in rodents, single oral administration of cefdinir at a dose of 5600 mg/kg did not lead to the development of any adverse reactions. Toxic signs and symptoms associated with overdose of other β-lactam antibiotics include nausea, vomiting, dyspeptic disorders, diarrhea, and seizures.

Treatment. Cefdinir is removed from the body during hemodialysis, which may be beneficial in severe toxic reactions caused by overdose, especially in patients with impaired renal function.

Side effects.

The following adverse reactions were observed during clinical trials in children with the following frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data):

Common – diarrhea, vaginal candidiasis, nausea, headache, abdominal pain, vaginitis;

Uncommon – rash, dyspepsia, flatulence, vomiting, defecation disorder, anorexia, constipation, dizziness, dry mouth, asthenia, insomnia, leukorrhea, candidiasis, pruritus, somnolence.

The following adverse reactions have been reported with the use of antibiotics of the cephalosporin class:

allergic reactions, anaphylaxis, Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, renal function disorders, toxic nephropathy, hepatic function disorders (including cholestasis), aplastic anemia, hemolytic anemia, hemorrhagic disorders, false positive urine glucose test, neutropenia, pancytopenia, and agranulocytosis. Symptoms of pseudomembranous colitis may appear both during and after completion of antibiotic therapy (see section "Special precautions for use").

Seizures have occurred with some cephalosporins, particularly in patients with impaired renal function who did not receive dose adjustment (see sections "Dosage and administration" and "Overdose"). If seizures occur, the drug should be discontinued. Anticonvulsant therapy may be initiated if clinically necessary.

Additional adverse reactions identified from post-marketing experience with cefdinir include:

Eye disorders: conjunctivitis;

Respiratory, thoracic and mediastinal disorders: acute respiratory failure, asthma attack, drug-induced pneumonia, eosinophilic pneumonia, idiopathic interstitial pneumonia;

Gastrointestinal disorders: stomatitis, upper gastrointestinal hemorrhage, peptic ulcer, intestinal obstruction, acute enterocolitis, bloody diarrhea, hemorrhagic colitis, melena, pseudomembranous colitis;

Hepatobiliary disorders: acute hepatitis, cholestasis, fulminant hepatitis, liver failure, jaundice, increased amylase levels;

Renal and urinary disorders: acute renal failure, nephropathy;

Cardiovascular disorders: heart failure, chest pain, myocardial infarction, hypertensive disease;

Blood and lymphatic system disorders: pancytopenia, granulocytopenia, leukopenia, thrombocytopenia, idiopathic thrombocytopenic purpura, hemolytic anemia, bleeding tendency, coagulation disorders, disseminated intravascular coagulation (DIC) syndrome;

Immune system disorders: shock, anaphylaxis (in rare cases, with fatal outcome), facial and laryngeal edema, sensation of suffocation, serum sickness, allergic vasculitis;

Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, erythema multiforme, nodular erythema;

Musculoskeletal and connective tissue disorders: involuntary movements, rhabdomyolysis;

General disorders: fever, loss of consciousness, potential interaction between cefdinir and diclofenac.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, as well as patients or their legal representatives are encouraged to report any 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 at a temperature not exceeding 25 °C in the original packaging.

Keep out of reach of children.

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

Packaging.

1 vial of powder for preparation of 60 mL of suspension with a dosing syringe in a cardboard package.

Prescription status. Prescription only.

Manufacturer.

Sens Laboratories Pvt. Ltd.

Manufacturer's address.

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

Marketing Authorization Holder.

ARTERIUM LTD LLC.

Address of the Marketing Authorization Holder.

139 Saksaganskogo St., Kyiv, 01032, Ukraine.