Cefdinir

CEFDINIR- cefdinir powder, for suspension
Preferred Pharmaceuticals Inc.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefdinir and other antibacterial drugs, cefdinir should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTION

Cefdinir for Oral Suspension USP contains the active ingredient cefdinir, an extended-spectrum, semisynthetic cephalosporin, for oral administration. Chemically, cefdinir is [6R-[6α, 7β (Z)]]-7-[[(2-amino-4-thiazolyl)(hydroxyimino)acetyl]amino]-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. Cefdinir is a white to slightly brownish-yellow solid. It is slightly soluble in dilute hydrochloric acid and sparingly soluble in 0.1 M pH 7.0 phosphate buffer. The empirical formula is C14 H13 N5 O5 S2 and the molecular weight is 395.42. Cefdinir has the structural formula shown below:

cefdinir-structure
(click image for full-size original)

Cefdinir for Oral Suspension USP, after reconstitution, contains 125 mg cefdinir per 5 mL or 250 mg cefdinir per 5 mL and the following inactive ingredients: sucrose, sodium benzoate, xanthan gum, guar gum, colloidal silicone dioxide, magnesium stearate, sodium citrate anhydrous, citric acid anhydrous and strawberry flavoring.

CLINICAL PHARMACOLOGY

Pharmacokinetics and Drug Metabolism
Absorption
Oral Bioavailability
Maximal plasma cefdinir concentrations occur 2 to 4 hours postdose following capsule or suspension administration. Plasma cefdinir concentrations increase with dose, but the increases are less than dose-proportional from 300 mg (7 mg/kg) to 600 mg (14 mg/kg). Following administration of suspension to healthy adults, cefdinir bioavailability is 120% relative to capsules. Estimated bioavailability of cefdinir capsules is 21% following administration of a 300 mg capsule dose, and 16% following administration of a 600 mg capsule dose. Estimated absolute bioavailability of cefdinir suspension is 25%. Cefdinir oral suspension of 250 mg/5 mL strength was shown to be bioequivalent to the 125 mg/5 mL strength in healthy adults under fasting conditions.
Effect of Food
The Cmax and AUC of cefdinir from the capsules are reduced by 16% and 10%, respectively, when given with a high-fat meal. In adults given the 250 mg/5 mL oral suspension with a high-fat meal, the Cmax and AUC of cefdinir are reduced by 44% and 33%, respectively. The magnitude of these reductions is not likely to be clinically significant because the safety and efficacy studies of oral suspension in pediatric patients were conducted without regard to food intake. Therefore, cefdinir may be taken without regard to food.
Cefdinir Suspension
Cefdinir plasma concentrations and pharmacokinetic parameter values following administration of single 7- and 14- mg/kg oral doses of cefdinir to pediatric subjects (age 6 months to 12 years) are presented in the following table:
Mean (±SD) Plasma Cefdinir Pharmacokinetic Parameter Values Following Administration of Suspension to Pediatric Subjects

Dose

Cmax(mcg /mL)

tmax(hr)

AUC(mcg .hr/mL)

7 mg /kg

2.30 (0 .6 5)

2.2(0 .6 )

8 .31(2.50 )

14 mg /kg

3.8 6 (0 .6 2)

1.8 (0 .4 )

13.4 (2.6 4 )

Multiple Dosing
Cefdinir does not accumulate in plasma following once- or twice-daily administration to subjects with normal renal function.
Distribution
The mean volume of distribution (Vdarea ) of cefdinir in adult subjects is 0.35 L/kg (±0.29); in pediatric subjects (age 6 months to 12 years), cefdinir Vdarea is 0.67 L/kg (±0.38). Cefdinir is 60% to 70% bound to plasma proteins in both adult and pediatric subjects; binding is independent of concentration.
Skin Blister
In adult subjects, median (range) maximal blister fluid cefdinir concentrations of 0.65 (0.33 to 1.1) and 1.1 (0.49 to 1.9) mcg/mL were observed 4 to 5 hours following administration of 300- and 600- mg doses, respectively. Mean (±SD) blister Cmax and AUC (0-∞) values were 48% (±13) and 91% (±18) of corresponding plasma values.
Tonsil Tissue
In adult patients undergoing elective tonsillectomy, respective median tonsil tissue cefdinir concentrations 4 hours after administration of single 300- and 600- mg doses were 0.25 (0.22 to 0.46) and 0.36 (0.22 to 0.80) mcg/g. Mean tonsil tissue concentrations were 24% (±8) of corresponding plasma concentrations.
Sinus Tissue
In adult patients undergoing elective maxillary and ethmoid sinus surgery, respective median sinus tissue cefdinir concentrations 4 hours after administration of single 300- and 600- mg doses were < 0.12 (< 0.12 to 0.46) and 0.21 (< 0.12 to 2.0) mcg/g. Mean sinus tissue concentrations were 16% (±20) of corresponding plasma concentrations.
Lung Tissue
In adult patients undergoing diagnostic bronchoscopy, respective median bronchial mucosa cefdinir concentrations 4 hours after administration of single 300- and 600- mg doses were 0.78 (< 0.06 to 1.33) and 1.14 (< 0.06 to 1.92) mcg/mL, and were 31% (±18) of corresponding plasma concentrations. Respective median epithelial lining fluid concentrations were 0.29 (< 0.3 to 4.73) and 0.49 (< 0.3 to 0.59) mcg/mL, and were 35% (±83) of corresponding plasma concentrations.
Middle Ear Fluid
In 14 pediatric patients with acute bacterial otitis media, respective median middle ear fluid cefdinir concentrations 3 hours after administration of single 7- and 14- mg/kg doses were 0.21 (< 0.09 to 0.94) and 0.72 (0.14 to 1.42) mcg/mL. Mean middle ear fluid concentrations were 15% (±15) of corresponding plasma concentrations.
CSF
Data on cefdinir penetration into human cerebrospinal fluid are not available.
Metabolism and Excretion
Cefdinir is not appreciably metabolized. Activity is primarily due to parent drug. Cefdinir is eliminated principally via renal excretion with a mean plasma elimination half-life (t1/2 ) of 1.7 (±0.6) hours. In healthy subjects with normal renal function, renal clearance is 2.0 (±1.0) mL/min/kg, and apparent oral clearance is 11.6 (±6.0) and 15.5 (±5.4) mL/min/kg following doses of 300- and 600- mg, respectively. Mean percent of dose recovered unchanged in the urine following 300- and 600- mg doses is 18.4% (±6.4) and 11.6% (±4.6), respectively. Cefdinir clearance is reduced in patients with renal dysfunction (see Special Populations: Patients with Renal Insufficiency).
Because renal excretion is the predominant pathway of elimination, dosage should be adjusted in patients with markedly compromised renal function or who are undergoing hemodialysis (see DOSAGE AND ADMINISTRATION).
Special Populations
Patients with Renal Insufficiency
Cefdinir pharmacokinetics were investigated in 21 adult subjects with varying degrees of renal function. Decreases in cefdinir elimination rate, apparent oral clearance (CL/F), and renal clearance were approximately proportional to the reduction in creatinine clearance (CLcr). As a result, plasma cefdinir concentrations were higher and persisted longer in subjects with renal impairment than in those without renal impairment. In subjects with CLcr between 30 and 60 mL/min, Cmax and t1/2 increased by approximately 2-fold and AUC by approximately 3-fold. In subjects with CLcr < 30 mL/min, Cmax increased by approximately 2-fold, t1/2 by approximately 5-fold, and AUC by approximately 6-fold. Dosage adjustment is recommended in patients with markedly compromised renal function (creatinine clearance < 30 mL/min; see DOSAGE AND ADMINISTRATION).
Hemodialysis
Cefdinir pharmacokinetics were studied in 8 adult subjects undergoing hemodialysis. Dialysis (4 hours duration) removed 63% of cefdinir from the body and reduced apparent elimination t1/2 from 16 (±3.5) to 3.2 (±1.2) hours. Dosage adjustment is recommended in this patient population (see DOSAGE AND ADMINISTRATION).
Hepatic Disease
Because cefdinir is predominantly renally eliminated and not appreciably metabolized, studies in patients with hepatic impairment were not conducted. It is not expected that dosage adjustment will be required in this population.
Geriatric Patients
The effect of age on cefdinir pharmacokinetics after a single 300- mg dose was evaluated in 32 subjects 19 to 91 years of age. Systemic exposure to cefdinir was substantially increased in older subjects (N=16), Cmax by 44% and AUC by 86%. This increase was due to a reduction in cefdinir clearance. The apparent volume of distribution was also reduced, thus no appreciable alterations in apparent elimination t1/2 were observed (elderly: 2.2 ± 0.6 hours vs young: 1.8 ± 0.4 hours). Since cefdinir clearance has been shown to be primarily related to changes in renal function rather than age, elderly patients do not require dosage adjustment unless they have markedly compromised renal function (creatinine clearance < 30 mL/min, see Patients with Renal Insufficiency, above).
Gender and Race
The results of a meta-analysis of clinical pharmacokinetics (N=217) indicated no significant impact of either gender or race on cefdinir pharmacokinetics.
Microbiology:
Mechanism of Action
As with other cephalosporins, bactericidal activity of cefdinir results from inhibition of cell wall synthesis. Cefdinir is stable in the presence of some, but not all, β-lactamase enzymes. As a result, many organisms resistant to penicillins and some cephalosporins are susceptible to cefdinir.
Mechanism of Resistance
Resistance to cefdinir is primarily through hydrolysis by some β-lactamases, alteration of penicillin-binding proteins (PBPs) and decreased 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) H. influenza strains are typically non-susceptible to cefdinir.
Antimicrobial Activity
Cefdinir has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in INDICATIONS AND USAGE.
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 exhibits in vitro minimum inhibitory concentrations (MICs) of 1 mcg/mL or less against (≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of cefdinir in treating clinical infections due to 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
Susceptibility Testing
For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

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