Rodinir

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RODINIR (RODINIR)

Composition:

Active substance: cefdinir;

1 hard capsule contains cefdinir 300 mg;

Excipients: calcium carmellose, polyoxystearate 40, colloidal anhydrous silicon dioxide, magnesium stearate; hard gelatin capsule: iron oxide black (E 172), titanium dioxide (E 171), gelatin.

Pharmaceutical form. Hard capsules.

Main physicochemical properties: hard gelatin capsules, size № 1, body grey in color, cap black in color, containing powder from white to light yellow.

Pharmacotherapeutic group.

Antibacterials for systemic use. Other beta-lactam antibiotics. Third-generation cephalosporins. ATC code J01D D15.

Pharmacological properties.

Pharmacodynamics.

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

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

The antimicrobial spectrum of cefdinir includes:

Aerobic gram-positive microorganisms: Staphylococcus aureus (only methicillin-susceptible strains), Streptococcus pneumoniae (only penicillin-susceptible strains), Streptococcus pyogenes;

Aerobic gram-negative microorganisms: Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis.

The minimum inhibitory concentration (MIC) of cefdinir in vitro is 1 mcg/mL or less for ≥90% of strains of the following microorganisms; however, its safety and efficacy in treating infections caused by these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic gram-positive microorganisms: Staphylococcus epidermidis, Streptococcus agalactiae, Streptococcus group viridans.

Aerobic gram-negative microorganisms: Citrobacter koseri, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis.

Cefdinir is inactive against most strains of Enterobacter spp., Pseudomonas spp., Enterococcus spp., penicillin-resistant streptococcal strains, and methicillin-resistant staphylococcal strains. Ampicillin-resistant strains of H. influenzae (non-beta-lactamase-producing) are generally insensitive to cefdinir.

Pharmacokinetics.

Absorption.

The time to reach maximum plasma concentration (Tmax) of cefdinir after oral administration ranges from 2 to 4 hours. Plasma cefdinir concentrations increase with increasing dose, although the increase becomes less proportional within the dose range of 300 mg (7 mg/kg) to 600 mg (14 mg/kg). The bioavailability of cefdinir following oral administration of 600 mg capsules is 16%.

When cefdinir is taken with a high-fat meal, the maximum plasma concentration (Cmax) and the area under the plasma concentration–time curve (AUC) decrease by 16% and 10%, respectively. This reduction is considered clinically insignificant. Therefore, cefdinir can be administered independently of food intake.

The mean (± SD [standard deviation]) pharmacokinetic parameters of cefdinir in plasma following administration of 600 mg capsules in adults are shown below.

Cmax (μg/ml)	Tmax (h)	AUC (μg×h/ml)
2.87	3	11.1
(1.01)	(0.66)	(3.87)

With single and twice-daily dosing in patients with normal renal function, cefdinir does not accumulate in plasma.

Distribution.

The mean volume of distribution (Vdarea) of cefdinir in adult patients is 0.35 L/kg (± 0.29). The extent of cefdinir binding to plasma proteins in both adults and children ranges from 60% to 70% and is independent of cefdinir concentration.

Skin bullae. In adults, the mean maximum concentration of cefdinir in bulla fluid was 1.1 (0.49–1.9) mcg/mL, observed 4–5 hours after a 600 mg dose. Mean (± standard deviation [SD]) values of Cmax and AUC (0–∞) were 48% (± 13) and 91% (± 18), respectively, of the corresponding plasma values.

Tonsils. In adult patients following scheduled tonsillectomy, the mean maximum concentration of cefdinir in tonsillar tissue was 0.36 (0.22–0.8) mcg/mL, observed 4 hours after a single 600 mg dose. Mean (± SD) tissue concentrations in tonsils were 24% (± 8) of the corresponding plasma concentrations.

Paranasal sinuses. In adult patients following scheduled maxillary and ethmoid sinus surgery, the mean maximum concentration of cefdinir in sinus tissue was 0.21 (< 0.12–2) mcg/mL, observed 4 hours after a single 600 mg dose. Mean (± SD) tissue concentrations in sinuses were 16% (± 20) of the corresponding plasma concentrations.

Lungs. In adult patients following diagnostic bronchoscopy, the mean maximum concentration of cefdinir in bronchial mucosa was 1.14 (< 0.06–1.92) mcg/mL, observed 4 hours after a single 600 mg dose, and was 31% (± 18) of the corresponding plasma concentrations. The mean maximum concentration in epithelial lining fluid was 0.49 (< 0.3–0.59) mcg/mL, representing 35% (± 83) of plasma concentrations.

Middle ear. In 14 pediatric patients with acute bacterial otitis media, the mean maximum concentration of cefdinir in middle ear fluid was 0.72 (0.14–1.42) mcg/mL, observed 3 hours after single doses of 7 and 14 mg/kg. Mean (± SD) concentrations in middle ear fluid were 15% (± 15) of the corresponding plasma concentrations.

There are no data on penetration of cefdinir into cerebrospinal fluid.

Metabolism and elimination.

Cefdinir undergoes no significant metabolism. It is primarily eliminated by the kidneys. The mean elimination half-life (T1/2) is 1.7 (± 0.6) hours. In healthy volunteers with normal renal function, after a 600 mg dose of cefdinir, renal clearance (creatinine clearance [CCr]) is 2.0 (± 1.0) mL/min/kg, and oral clearance is 15.5 (± 5.4) mL/min·kg. The mean percentage of the administered dose excreted unchanged in urine after a 600 mg dose is 11.6% (± 4.6). Cefdinir clearance is reduced in patients with impaired renal function.

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

Patients with renal impairment.

In patients with CCr of 30 to 60 mL/min, Cmax and T1/2 are approximately doubled, and AUC is increased approximately 3-fold. In subjects with CCr < 30 mL/min, Cmax increases approximately 2-fold, T1/2 increases approximately 5-fold, and AUC increases approximately 6-fold. Dosage adjustment is recommended for patients with severe renal impairment (CCr < 30 mL/min).

Patients on hemodialysis.

During dialysis (lasting 4 hours), 63% of cefdinir is removed from the body, and T1/2 decreases from 16 (± 3.5) to 3.2 (± 1.2) hours. Dosage adjustment is recommended for patients on hemodialysis.

Patients with hepatic impairment.

Since cefdinir is primarily eliminated by the kidneys and undergoes negligible metabolism, studies in patients with hepatic impairment have not been conducted. Dosage adjustment in such patients is not anticipated.

Elderly patients.

Systemic exposure to cefdinir is significantly increased in elderly individuals: Cmax and AUC are increased by 44% and 86%, respectively. This is due to reduced clearance. The volume of distribution is also reduced. However, no significant change in the mean elimination half-life of cefdinir is observed (elderly patients: 2.2 ± 0.6 hours; young patients: 1.8 ± 0.4 hours). Since cefdinir clearance is primarily related to changes in renal function rather than age, dosage adjustment in elderly patients is not required.

Gender and race.

A meta-analysis of pharmacokinetic clinical study results (N = 217) showed no significant effect of either gender or race on the pharmacokinetics of cefdinir.

Clinical characteristics.

Indications.

Treatment of mild to moderate infections caused by susceptible microorganisms.

Adults and children aged 13 years and older

Community-acquired pneumonia caused by:

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

Exacerbation of chronic bronchitis caused by:

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

Acute sinusitis caused by:

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

Pharyngitis/tonsillitis caused by:

• Streptococcus pyogenes.

Uncomplicated skin and soft tissue infections caused by:

• Staphylococcus aureus (including beta-lactamase-producing strains);
• Streptococcus pyogenes.

Contraindications.

Hypersensitivity to cefdinir, other cephalosporins, or any component of the medicinal product.

Interaction with other medicinal products and other types of interactions.

The following interactions are possible when cefdinir is used concomitantly with other medicinal products.

Antacids (aluminum- or magnesium-containing).

Concomitant administration with antacids reduces Cmax and the extent of cefdinir absorption by approximately 40%. The time to reach Cmax is also prolonged by 1 hour. To avoid this interaction, cefdinir should be taken at least 2 hours before or 2 hours after antacid administration.

Iron supplements and iron-fortified products.

Concomitant administration with iron supplements containing 60 mg of elemental iron (as FeSO4) or with vitamins containing 10 mg of elemental iron reduces cefdinir absorption by 80% and 31%, respectively. To avoid this interaction, cefdinir should be taken at least 2 hours before or 2 hours after administration of iron supplements.

The effect of iron-fortified food products on cefdinir absorption has not been studied.

Reddish discoloration of stools has been reported in patients taking cefdinir. In many cases, patients were also taking iron-containing products. The red coloration may be due to the formation in the gastrointestinal tract of a complex between cefdinir or its degradation products and unabsorbed iron.

Probenecid.

Concomitant use with probenecid may impair renal excretion of cefdinir (as with other cephalosporins), resulting in a doubling of AUC, a 54% increase in Cmax, and a 50% increase in T1/2.

Interaction with laboratory tests.

During cefdinir therapy, false-positive results in the urine ketone test may occur when using nitroprusside reagents.

Cefdinir may also cause false-positive results when testing for urinary glucose using Benedict's solution or Fehling's reagent. Urine glucose should therefore be tested using an enzymatic method only.

Cephalosporins may occasionally cause false-positive results in the Coombs test.

Special precautions.

To reduce the rate of development of antibiotic resistance, the medicinal product should be used only for the treatment or prevention of infections caused by susceptible bacteria. When information on bacterial culture results and sensitivity testing is available, it should be taken into account when selecting or changing antibacterial therapy. In the absence of such data, empirical choice of therapy may be influenced by local epidemiological data and local patterns of susceptibility.

Cefdinir is effective in the treatment of oropharyngeal infections caused by Streptococcus pyogenes (S. pyogenes). However, the efficacy of cefdinir for the prevention of rheumatic fever following pharyngitis/tonsillitis caused by S. pyogenes has not been established.

Administration of cefdinir in the absence of proven or strongly suspected bacterial infection, or its prophylactic use, is unlikely to provide benefit to the patient and increases the risk of developing antibiotic resistance.

As with other broad-spectrum antibiotics, prolonged treatment with cefdinir may lead to overgrowth of non-susceptible microorganisms. Close monitoring of the patient is required. If superinfection occurs, appropriate alternative therapy should be initiated.

Effect on the immune system.

Prior to initiating treatment, a history of hypersensitivity reactions to cefdinir, other cephalosporins, penicillins, or other medicinal products should be excluded.

Extreme caution should be exercised when administering the medicinal product to patients with a history of penicillin hypersensitivity, as cross-reactivity between beta-lactam antibiotics has been demonstrated in approximately 10% of patients with a history of allergic reactions to penicillin.

If hypersensitivity reactions occur, the medicinal product should be discontinued. In the event of severe allergic reactions, administration of adrenaline and other emergency measures may be required, including oxygen supply, intravenous fluids, antihistamines, corticosteroids, pressor amines, and ensuring airway patency, as clinically indicated.

Effect on the gastrointestinal tract.

Diarrhea associated with Clostridium difficile (C. difficile) has been reported during or following the use of nearly all antibacterial agents, including cefdinir, with severity ranging from mild diarrhea to fatal colitis. Antibacterial treatment alters the normal flora of the colon, leading to overgrowth of C. difficile. C. difficile produces toxins A and B, which contribute to the development of pseudomembranous colitis. A hyper-toxin-producing strain of C. difficile is associated with increased morbidity and mortality, as this infection may be resistant to antimicrobial therapy and may necessitate colectomy.

Pseudomembranous colitis should be considered in all patients who develop diarrhea following antibiotic use. Careful medical history is essential, as pseudomembranous colitis has been reported to occur more than two months after antibiotic administration.

If pseudomembranous colitis is suspected or confirmed, the medicinal product should be discontinued. Depending on the clinical condition, appropriate management may include administration of fluids and electrolytes, protein supplementation, antibiotic therapy effective against C. difficile, and surgical evaluation.

Use in patients with a history of colitis.

The medicinal product should be used with caution in such patients.

Use in patients with renal impairment.

The daily dose of the medicinal product should be reduced in patients with renal impairment (CrCl < 30 mL/min), as administration at the recommended doses may result in a significant increase in plasma concentrations and elimination half-life of cefdinir.

Use during pregnancy or breastfeeding.

Animal reproduction studies have not revealed any teratogenic effects.

There are no adequate and well-controlled studies of cefdinir use in pregnant women. Data on the effect of cefdinir on labor are lacking.

The medicinal product may be used during pregnancy only if clearly needed and the potential benefit justifies the potential risk to the fetus.

When cefdinir is administered at a dose of 600 mg, it is not detected in breast milk.

Ability to affect reaction speed when driving or operating machinery.

The medicinal product does not affect the ability to drive or operate machinery.

Method of administration and dosage.

The medicinal product is intended for oral administration. Capsules can be taken regardless of food intake.

Adults and children aged 13 years and older

The recommended dosage regimen of the medicinal product and duration of treatment for infections are indicated in the table below. The total daily dose for treatment of all infections is 600 mg. Administration of cefdinir at a dose of 600 mg once daily for 10 days is as effective as administration of 300 mg twice daily. Once-daily administration of cefdinir has not been studied in the treatment of pneumonia and skin infections; therefore, in these cases the medicinal product should be administered twice daily.

Table

Type of infection	Dosage	Duration
Community-acquired pneumonia	300 mg every 12 hours	10 days
Acute exacerbation of chronic bronchitis	300 mg every 12 hours or 600 mg every 24 hours	5–10 days or 10 days
Acute sinusitis	300 mg every 12 hours or 600 mg every 24 hours	10 days
Pharyngitis/tonsillitis	300 mg every 12 hours or 600 mg every 24 hours	5–10 days or 10 days
Uncomplicated skin and soft tissue infections	300 mg every 12 hours	10 days

Patients with renal impairment

For adult patients with creatinine clearance (CrCl) < 30 mL/min, the medicinal product should be administered at a dose of 300 mg once daily.

The formula given below may be used to estimate CrCl in adult patients. Plasma creatinine should reflect a steady-state renal function.

[140 – age (in years)] × body weight (kg) 72 × plasma creatinine (mg/dL)

(× 0.85 for women)

CC (ml/min) =

For children with CC < 30 ml/min/1.73 m², the drug should be administered at a dose of 7 mg/kg (up to 300 mg) once daily.

To estimate CC in children, the following formula can be used.

CC (ml/min/1.73 m2) = 0.55 × height (cm)_________________

plasma creatinine (mg/dL)

Patients on hemodialysis

For patients on regular hemodialysis, the recommended initial dose of the medicinal product is 300 mg or 7 mg/kg every other day. Administer 300 mg (or 7 mg/kg) of cefdinir at the end of each hemodialysis session; subsequent doses (300 mg or 7 mg/kg) should be administered every other day.

Patients with hepatic impairment

Dosage adjustment is not required for these patients.

Elderly patients

There is no need for dosage adjustment in these patients.

Children

The medicinal product can be administered to children aged 13 years and older.

Overdose

There are no data regarding cefdinir overdose in humans. In acute toxicity studies in rodents, single oral administration of cefdinir at a dose of 5600 mg/kg did not cause adverse reactions. In cases of overdose with other cephalosporins, symptoms such as nausea, vomiting, gastric discomfort, diarrhea, and seizures have been reported.

Cefdinir is eliminated from the body by hemodialysis, which may be beneficial in the event of serious toxic reactions caused by overdose, especially in patients with impaired renal function.

Adverse Reactions

The following adverse reactions were observed during clinical trials with cefdinir:

Common (≥ 1/100 to < 1/10): diarrhea, vaginal candidiasis, nausea, headache, abdominal pain, vaginitis;

Uncommon (≥ 1/1000 to < 1/100): rash, dyspepsia, flatulence, vomiting, changes in bowel movements, anorexia, constipation, dizziness, dry mouth, asthenia, insomnia, leukorrhea, candidiasis, pruritus, somnolence.

The following adverse reactions have been identified based on post-marketing experience with cefdinir:

Blood and lymphatic system disorders: pancytopenia, granulocytopenia, leukopenia, thrombocytopenia, idiopathic thrombocytopenic purpura, hemolytic anemia, bleeding tendency, coagulation disorders, generalized thrombohemorrhagic syndrome;

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

Nervous system disorders: loss of consciousness, involuntary movements;

Eye disorders: conjunctivitis;

Cardiac disorders: heart failure, chest pain, myocardial infarction;

Vascular disorders: hypertension;

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

Gastrointestinal disorders: stomatitis, increased amylase levels, acute enterocolitis, hemorrhagic diarrhea, hemorrhagic colitis, melena, pseudomembranous colitis, upper gastrointestinal tract bleeding, peptic ulcer, intestinal obstruction;

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

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

Renal and urinary disorders: acute renal failure, nephropathy;

Musculoskeletal and connective tissue disorders: rhabdomyolysis;

General disorders and administration site conditions: fever.

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

Blood and lymphatic system disorders: aplastic anemia, hemolytic anemia, hemorrhagic disorders, neutropenia, pancytopenia, agranulocytosis;

Immune system disorders: allergic reactions, anaphylaxis;

Hepatobiliary disorders: liver function abnormalities including cholestasis;

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

Renal and urinary disorders: renal function abnormalities, toxic nephropathy;

Investigations: false-positive urine glucose test.

Pseudomembranous colitis may develop during or after antibiotic treatment.

Seizures have been reported with some cephalosporins, particularly in patients with impaired renal function who have not had their dosage adjusted. If seizures occur, the drug should be discontinued. Anticonvulsant therapy may be initiated if clinically indicated.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after the medicine has been authorized is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals, 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: https://aisf.dec.gov.ua.

Shelf life

3 years.

Storage conditions

Store at a temperature not exceeding 25 °C in a place inaccessible to children.

Packaging

10 capsules per blister; 1 or 2 blisters per cardboard box.

Prescription status

Prescription only.

Manufacturer

PharmaVision San. ve Tic. A.S., Turkey.

Manufacturer's address

Davutpasa Cad. No:145 Zeytinburnu Istanbul, Turkey.

Marketing Authorization Holder

WORLD MEDICINE, LLC, Ukraine.