Xevaneer® (cefdinir) Oral Suspension is indicated for the treatment of patients with mild to moderate infections caused by susceptible strains of the designated micro-organisms in the conditions listed below.

Adults and Adolescents
Community-Acquired Pneumonia caused by Haemophilus influenzae (including βlactamase producing strains), Haemophilus parainfluenzae (including β -lactamase producing strains), Streptococcus pneumoniae (penicillin-susceptible strains only), and Moraxella catarrhalis (including β -lactamase producing strains).

Acute Exacerbations of Chronic Bronchitis caused by Haemophilus influenza (including β -lactamase producing strains), Haemophilus parainfluenzae (including β -lactamase producing strains),Streptococcus pneumoniae (penicillin-susceptible strains only), Moraxella catarrhalis (including β -lactamase producing strains).

Acute Maxillary 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.

NOTE: Cefdinir is effective in the eradication of S. pyogenes from the oropharynx. Cefdinir has not, however, been studied for the prevention of rheumatic fever following S. pyogenes pharyngitis/tonsillitis. Only intramuscular penicillin has been demonstrated to be effective for the prevention of rheumatic fever. Uncomplicated Skin and Skin Structure Infections caused by Staphylococcus aureus (including β -lactamase producing strains) and Streptococcus pyogenes.

Pediatric PatientsAcute 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). Pharyngitis/Tonsillitis caused by Streptococcus pyogenes NOTE: Cefdinir is effective in the eradication of S. pyogenes from the oropharynx. Cefdinir has not, however, been studied for the prevention of rheumatic fever following S. pyogenes pharyngitis/tonsillitis. Only intramuscular penicillin has been demonstrated to be effective for the prevention of rheumatic fever. Uncomplicated Skin and Skin Structure Infections caused by Staphylococcus aureus (including β-lactamase producing strains) and Streptococcus pyogenes

Powder for Oral Suspension
The recommended dosage and duration of treatment for infections in pediatric patients are described in the following chart; the total daily dose for all infections is 14 mg/kg, up to a maximum dose of 600 mg per day. Once-daily dosing for 10 days is as effective as BID dosing. Once-daily dosing has not been studied in skin infections; therefore, Xevaneer® Oral Suspension should be administered twice daily in this infection.

Xevaneer^® Oral Suspension may be administered without regard to meals.

Pediatric Patients (Age 6 Months Through 12 Years)

Xevaneer^® for oral suspension pediatric dosage chart

^a Pediatric patient who weigh ³43 kg should receive the maximum daily dose of 600 mg.

Patients With Renal Insufficiency

Creatinine clearance is difficult to measure in outpatients. However, the following formula may be used to estimate creatinine clearance (CLcr) in adult patients. For estimates to be valid, serum creatinine levels should reflect steady-state levels of renal function.

Males:

Females:

       CLcr = 0.85 * above value

Where creatinine clearance is in mL/min, age is in years, weight is in kilograms, and serum creatinine is in mg/dL³

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

Patients on hemodialysis

Hemodialysis removes cefdinir from the body. In patients maintained on chronic hemodialysis, the recommended initial dosage regimen is a 300 mg or 7 mg /kg dose every other day. At the conclusion of each hemodialysis session, 300 mg (or 7mg /kg) should be given. Subsequent doses (300 mg or 7 mg /kg) are then administered every other day.

DIRECTIONS FOR MIXING CEFDINIR FOR ORAL SUSPENSION

Pediatric Use

Safety and efficacy in neonates and infants less than 6 months of age have not been established. Use of cefdinir for the treatment of acute maxillary sinusitis in pediatric patients (age 6 months through 12 years) is supported by evidence from adequate and well-controlled studies in adults and adolescents, the similar pathophysiology of acute sinusitis in adult and pediatric patients, and comparative pharmacokinetic data in the pediatric population.

Geriatric Use

Efficacy is comparable in geriatric patients and younger adults. While cefdinir has been well-tolerated in all age groups, in clinical trials geriatric patients experienced a lower rate of adverse events, including diarrhea, than younger adults. Dose adjustment in elderly patients is not necessary unless renal function is markedly compromised.

For reconstitution:

·         Invert the bottle and shake content to loosen powder, add pre-boiled cooled water to the mark, and shake well, then add more water if necessary up to the mark and shake well until a homogeneous suspension is obtained.

·         When first reconstituted, allow to stand for five minutes to ensure full dispersion.

·         Shake well before use.

Before therapy with Xevaneer^® (cefdinir) is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cefdinir, other cephalosporins, penicillins, or other drugs. If cefdinir is to be given to penicillin-sensitive patients, caution should be exercised because cross-hypersensitivity among β-lactam antibiotics has been clearly documented 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. serious acute hypersensitivity reactions may require treatment with epinephrine and other emergency measures, including oxygen, intravenous fluids, intravenous antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including cefdinir, and may range in severity from mild- to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of “antibiotic-associated colitis”.

After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile.

PRECAUTIONS

General

As with other broad-spectrum antibiotics, prolonged treatment may result in the possible emergence and overgrowth of resistant organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate alternative therapy should be administered.

Cefdinir, as with other broad-spectrum antimicrobials (antibiotics), should be prescribed with caution in individuals with a history of colitis.

In patients with transient or persistent renal insufficiency (creatinine clearance <30 mL/min), the total daily dose of cefdinir should be reduced because high and prolonged plasma concentrations of cefdinir can result following recommended doses

Information for Patients

Antacids containing magnesium or aluminum interfere with the absorption of cefdinir. If this type of antacid is required during cefdinir therapy, cefdinir should be taken at least 2 hours before or after the antacid.

Iron supplements, including multivitamins that contain iron, interfere with the absorption of cefdinir. If iron supplements are required during cefdinir therapy, cefdinir should be taken at least 2 hours before or after the supplement.

Iron-fortified infant formula does not significantly interfere with the absorption of cefdinir. Therefore, Xevaneer^® Oral Suspension can be administered with iron fortified infant formula.

Xevaneer^® suspension contains approximately 2.9 grams sucrose per 5 ml;

·      This should be taken into account in patients with diabetes mellitus.

·      If you have been told by your doctor that you have intolerance to some sugars, contact your doctor before taking this medicinal product.

·      Sucrose may be harmful to the teeth.

Antacids: (aluminum- or magnesium-containing): Concomitant administration of 300-mg cefdinir capsules with 30 mL Maalox® TC suspension reduces the rate (Cmax) and extent (AUC) of absorption by approximately 40%. Time to reach Cmax is also prolonged by 1 hour. There are no significant effects on cefdinir pharmacokinetics if the antacid is administered 2 hours before or 2 hours after cefdinir. If antacids are required during cefdinir therapy, cefdinir should be taken at least 2 hours before or after the antacid.

Probenecid: As with other β-lactam antibiotics, probenecid inhibits the renal excretion of cefdinir, resulting in an approximate doubling in AUC, a 54% increase in peak cefdinir plasma levels, and a 50% prolongation in the apparent elimination half-life.

Iron Supplements and Foods Fortified with Iron: Concomitant administration of cefdinir with a therapeutic iron supplement containing 60 mg of elemental iron (as FeSO4) or vitamins supplemented with 10 mg of elemental iron reduced extent of absorption by 80% and 31%, respectively. If iron supplements are required during cefdinir therapy, cefdinir should be taken at least 2 hours before or after the supplement. The effect of foods highly fortified with elemental iron (primarily iron-fortified breakfast cereals) on cefdinir absorption has not been studied. Concomitantly administered iron-fortified infant formula (2.2 mg elemental iron/6 oz) has no significant effect on cefdinir pharmacokinetics. Therefore, cefdinir for Oral Suspension can be administered with iron-fortified infant formula.

There have been rare reports of reddish stools in patients who have received cefdinir in Japan. The reddish color is due to the formation of a nonabsorbable complex between cefdinir or its breakdown products and iron in the gastrointestinal tract.

Drug/Laboratory Test Interactions

A false-positive reaction for ketones in the urine may occur with tests using nitroprusside, but not with those using nitroferricyanide. The administration of cefdinir may result in a false-positive reaction for glucose in urine using Clinitest®, Benedict’s solution, or Fehling's solution. It is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as Clinistix® or Tes-Tape®) be used. Cephalosporins are known to occasionally induce a positive direct Coombs’ test.

Pregnancy - Teratogenic Effects

Pregnancy Category B: Cefdinir was not teratogenic in rats at oral doses up to 1000 mg/kg/day (70 times the human dose based on mg/kg/day, 11 times based on mg/m2/day) or in rabbits at oral doses up to 10 mg/kg/day (0.7 times the human dose based on mg/kg/day, 0.23 times based on mg/m2/day). Maternal toxicity (decreased body weight gain) was observed in rabbits at the maximum tolerated dose of 10 mg/kg/day without adverse effects on offspring. Decreased body weight occurred in rat fetuses at ³ 100 mg/kg/day, and in rat offspring at ³ 32 mg/kg/day. No effects were observed on maternal reproductive parameters or offspring survival, development, behavior, or reproductive function.

There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Labor and Delivery

Cefdinir has not been studied for use during labor and delivery.

Nursing Mothers

Following administration of single 600-mg doses, cefdinir was not detected in human breast milk.

In rats, fertility and reproductive performance were not affected by cefdinir at oral doses up to 1000 mg/kg/day (70 times the human dose based on mg/kg/day, 11 times based on mg/m2/day).

Adverse effects on the ability to drive or operate machinery have not been observed.

Clinical Trials – cefdinir for Oral Suspension (Pediatric Patients):

In clinical trials, 2289 pediatric patients (1783 US and 506 non-US) were treated with the recommended dose of cefdinir suspension (14 mg/kg/day). Most adverse events were mild and self-limiting. No deaths or permanent disabilities were attributed to cefdinir.

Forty of 2289 (2%) patients discontinued medication due to adverse events considered by the investigators to be possibly, probably, or definitely associated with cefdinir therapy.

Discontinuations were primarily for gastrointestinal disturbances, usually diarrhea.

Five of 2289 (0.2%) patients were discontinued due to rash thought related to cefdinir administration.

In the US, the following adverse events were thought by investigators to be possibly, probably, or definitely related to cefdinir suspension in multiple-dose clinical trials

(N = 1783 cefdinir-treated patients):

a 977 males, 806 females

b Laboratory changes were occasionally reported as adverse events

.

NOTE: In both cefdinir- and control-treated patients, rates of diarrhea and rash were higher in the youngest pediatric patients. The incidence of diarrhea in cefdinir-treated patients 2 years of age was 17% (95/557) compared with 4% (51/1226) in those >2 years old. The incidence of rash (primarily diaper rash in the younger patients) was 8% (43/557) in patients 2 years of age compared with 1% (8/1226) in those >2 years old.

Post marketing Experience

The following adverse experiences and altered laboratory tests, regardless of their relationship to cefdinir, have been reported during extensive postmarketing experience, beginning with approval in Japan in 1991: Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, erythema multiforme, erythema nodosum, conjunctivitis, stomatitis, acute hepatitis, cholestasis, fulminant hepatitis, hepatic failure, jaundice, increased amylase, shock, anaphylaxis, facial and laryngeal edema, feeling of suffocation, acute enterocolitis, bloody diarrhea, hemorrhagic colitis, melena, pseudomembranous colitis, pancytopenia, granulocytopenia, leukopenia, thrombocytopenia, idiopathic thrombocytopenic purpura, hemolytic anemia, acute respiratory failure, asthmatic attack, drug-induced pneumonia, eosinophilic pneumonia, idiopathic interstitial pneumonia, fever, acute renal failure, nephropathy, bleeding tendency, coagulation disorder, disseminated intravascular coagulation, upper GI bleed, peptic ulcer, ileus, loss of consciousness, allergic vasculitis, possible cefdinir-diclofenac interaction, cardiac failure, chest pain, myocardial infarction, hypertension, involuntary movements, and rhabdomyolysis.

Cephalosporin Class Adverse Events

The following adverse events and altered laboratory tests have been reported for cephalosporin-class antibiotics in general:

Allergic reactions, anaphylaxis, Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, renal dysfunction, toxic nephropathy, hepatic dysfunction including cholestasis, aplastic anemia, hemolytic anemia, hemorrhage, false-positive test for urinary glucose, neutropenia, pancytopenia, and agranulocytosis. Pseudomembranous colitis symptoms may begin during or after antibiotic treatment. Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced. If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.

To report any side effects:

·            National Pharmacovigilance and Drug Safety Centre (NPC)

-        Fax: + 966 112057662

-        Call NPC at + 966 112038222, Exts: 2317-2356-2353-2354-2334-2340

-        Toll free phone: 8002490000

-        E-mail: npc.drug@sfda.gov.sa

Website: www.sfda.gov.sa/npc

Information on cefdinir overdosage in humans is not available. In acute rodent toxicity studies, a single oral 5600-mg/kg dose produced no adverse effects. Toxic signs and symptoms following overdosage with other β-lactam antibiotics have included nausea, vomiting, epigastric distress, diarrhea, and convulsions. Hemodialysis removes cefdinir from the body. This may be useful in the event of a serious toxic reaction from overdosage, particularly if renal function is compromised.

Antibacterials for systemic use, other beta-lactam antibacterials, third-generation cephalosporins, ATC code: J01DD15.

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.

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

Aerobic Gram-Positive Microorganisms:

Staphylococcus aureus (including β-lactamase producing strains)

NOTE: Cefdinir is inactive against methicillin-resistant staphylococci.

Streptococcus pneumoniae (penicillin-susceptible strains only)

Streptococcus pyogenes

Aerobic Gram-Negative Microorganisms:

Haemophilus influenzae (including β-lactamase producing strains)

Haemophilus parainfluenzae (including β-lactamase producing strains)

Moraxella catarrhalis (including β-lactamase producing strains)

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

Cefdinir exhibits in vitro minimum inhibitory concentrations (MICs) of 1 μg/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.

Aerobic Gram-Positive Microorganisms:

Staphylococcus epidermidis (methicillin-susceptible strains only)

Streptococcus agalactiae

Viridans group streptococci

NOTE: Cefdinir is inactive against Enterococcus and methicillin-resistant

Staphylococcus species.

Aerobic Gram-Negative Microorganisms:

Citrobacter diversus

Escherichia coli

Klebsiella pneumoniae

Proteus mirabilis

NOTE: Cefdinir is inactive against Pseudomonas and Enterobacter species.

Susceptibility Tests:

Dilution Techniques: Quantitative methods are used to determine antimicrobial

minimum inhibitory concentrations (MICs). These MICs provide estimates of the

susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of cefdinir powder. The MIC values should be interpreted according to the following criteria:

For organisms other than Haemophilus spp. and Streptococcus spp:

For Haemophilus spp:a

For Streptococcus spp:

Streptococcus pneumoniae that are susceptible to penicillin (MIC £ 0.06 μg/mL), or streptococci other than S. pneumoniae that are susceptible to penicillin (MIC £ 0.12 μg/mL), can be considered susceptible to cefdinir. Testing of cefdinir against penicillin-intermediate or penicillin-resistant isolates is not recommended. Reliable interpretive criteria for cefdinir are not available.

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the

antimicrobial compound in the blood reaches the concentration usually achievable. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of laboratory procedures. Standard cefdinir powder should provide the following MIC values:

^c This quality control range is applicable only to H. influenzae

ATCC 49766 tested by a broth microdilution procedure using HTM.

Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 5-μg cefdinir to test the susceptibility of microorganisms to cefdinir.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5-μg cefdinir disk should be interpreted according to the following criteria:

For organisms other than Haemophilus spp. and Streptococcus spp:^d

d Because certain strains of Citrobacter, Providencia, and Enterobacter spp. have been reported to give false susceptible results with the cefdinir disk, strains of these genera should not be tested and reported with this disk.

For Haemophilus spp

e These zone diameter standards are applicable only to tests with Haemophilus spp. using HTM.²

f The current absence of data on resistant strains precludes defining any results other than “Susceptible.” Strains yielding “MIC deleted” results suggestive of a “nonsusceptible” category should be submitted to a reference laboratory for further testing.

For Streptococcus spp:

Isolates of Streptococcus pneumoniae should be tested against a 1-μg oxacillin disk.

Isolates with oxacillin zone sizes ³ 20 mm are susceptible to penicillin and can be considered susceptible to cefdinir. Streptococci other than S. pneumoniae should be tested with a 10-unit penicillin disk. Isolates with penicillin zone sizes ³ 28 mm are susceptible to penicillin and can be considered susceptible to cefdinir.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms to control the technical aspects of laboratory procedures. For the diffusion technique the 5-μg cefdinir disk should provide the following zone diameters in these laboratory quality control strains:

g This quality control range is applicable only to testing of H. influenzae

ATCC 49766 using HTM.

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%.

Effect of Food: Although the rate (Cmax) and extent (AUC) of cefdinir absorption from the capsules are reduced by 16% and 10%, respectively, when given with a high-fat meal, the magnitude of these reductions is not likely to be clinically significant. Therefore, cefdinir may be taken without regard to food.

Cefdinir Capsules: Cefdinir plasma concentrations and pharmacokinetic parameter values following administration of single 300- and 600-mg oral doses of cefdinir to adult subjects are presented in the following table:

Mean (± SD) Plasma Cefdinir Pharmacokinetic Parameter

Values Following Administration of Capsules to Adult Subjects

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-12 years) are presented in the following table:

Mean (±SD) Plasma Cefdinir Pharmacokinetic Parameter Values Following

Administration of Suspension to Pediatric Subjects

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-12 years), cefdinir Vd area 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 (0.33-1.1) and 1.1 (0.49-1.9) μg/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 (0.22-0.46) and 0.36 (0.22-0.80) μg/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 (<0.12-0.46) and 0.21 (<0.12-2.0) μg/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 (<0.06-1.33) and 1.14 (<0.06-1.92) μg/mL, and were 31% (±18) of corresponding plasma concentrations. Respective median epithelial lining fluid concentrations were 0.29 (<0.3-4.73) and 0.49 (<0.3-0.59) μg/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 (<0.09-0.94) and 0.72 (0.14-1.42) μg/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 (t½) 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

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.

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 t½ increased by approximately 2-fold and AUC by approximately 3-fold. In subjects with CLcr <30 mL/min, Cmax increased by approximately 2-fold, t½ by pproximately 5-fold, and AUC by approximately 6-fold. Dosage adjustment is recommended in patients with markedly compromised renal function (creatinine clearance <30 mL/min)

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 t½ from 16 (±3.5) to 3.2 (±1.2) hours. Dosage adjustment is recommended in this patient population

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 half-life 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).

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.

The carcinogenic potential of cefdinir has not been evaluated. No mutagenic effects were seen in the bacterial reverse mutation assay (Ames) or point mutation assay at the hypoxanthine-guanine phosphoribosyltransferase locus (HGPRT) in V79 Chinese hamster lung cells. No clastogenic effects were observed in vitro in the structural chromosome aberration assay in V79 Chinese hamster lung cells or in vivo in the micronucleus assay in mouse bone marrow. In rats, fertility and reproductive performance were not affected by cefdinir at oral doses up to 1000 mg/kg/day (70 times the human dose based on mg/kg/day, 11 times based on mg/m2/day).

Tribasic sodium citrate, colloidal anhydrous silica, magnesium stearate, sodium benzoate, citric acid, sucrose, xanthan gum, guar gum, strawberry flavor.

None known.

Do not store above 30°C. For suspension: Discard unused content 10 days after reconstitution

Glass amber bottle with a plastic CRC cap with induction enclosed in a carton box along with an insert. Xevaneer® suspension is available in bottles containing powder sufficient to prepare 40 ml or 80 ml suspension. Not all pack sizes may be marketed

Medicines should not be disposed of via wastewater or household waste.