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 susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Denacif® is indicated for the treatment of patients with mild to moderate infections caused by susceptible strains of the designated microorganisms in the conditions listed below.

Adults and Adolescents Community-Acquired Pneumonia

Caused by Haemophilus influenzae (including β-lactamase producing strains), Haemophilus parainfluenzae (including     β-lactamase      producing     strains), Streptococcus pneumonia

(penicillin-susceptible     strains       only),      and Moraxella catarrhalis (including     β-lactamase producing strains).

Acute Exacerbations of Chronic Bronchitis

Caused by Haemophilus influenzae (including β-lactamase producing strains), Haemophilus parainfluenzae (including     β-lactamase     producing     strains), Streptococcus pneumonia (penicillin-susceptible     strains       only),      and 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).

NOTE: For information on use in pediatric patients.

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 Patients

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).

Pharyngitis/Tonsillitis

Caused by Streptococcus pyogenes (see CLINICAL STUDIES).

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.

(See INDICATIONS AND USAGE for Indicated Pathogens)

Adults:

The recommended dosage and duration of treatment for infections in adults and adolescents are described in the following chart; the total daily dose for all infections is 600 mg. Once-daily

dosing for 10 days is as effective as b.i.d. dosing. Once-daily dosing has not been studied in pneumonia or skin infections; therefore, Denacif® capsules should be administered twice daily in these infections. Denacif® capsules may be taken without regard to meals.

Adults and Adolescents (Age 13 Years and Older)

Children:

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, Denacif® for oral suspension should be administered twice daily in this infection. Denacif® for oral suspension may be administered without regard to meals.

Pediatric Patients (Age 6 Months Through 12 Years)

Pediatric patients who weigh ≥43 kg should receive the maximum daily dose of 600 mg.

*Pediatric patients who weigh ≥ 4 3 kg should receive the maximum daily dose of 600 mg.

Patients with Renal Insufficiency

For adult patients with creatinine clearance <30 mL/min, the dose of Denacif® should be 300 mg given once daily.

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.

The following formula may be used to estimate creatinine clearance in pediatric patients:

In the above equation, creatinine clearance is in mL/min/1.73 m2, body length or height is in centimeters, and serum creatinine is in mg/dL.

For  pediatric  patients  with  a  creatinine  clearance  of  <30  mL/min/1.73  m2,  the  dose  of

Denacif® 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 7 mg/kg) should be given. Subsequent doses (300 mg or 7 mg/kg) are then administered every other day.

Method of the reconstitution for Denacif®

Invert the bottle and shake powder loose.

Add boiled and cooled water in two portions up to the mark indicated on the bottle, shake after each addition until a homogeneous suspension is achieved.

After reconstitution, the suspension should be used within 14 days. 

CLINICAL STUDIES

Community-Acquired Bacterial Pneumonia

In a controlled, double-blind study in adults and adolescents conducted in the U.S., cefdinir

b.i.d. was compared with cefaclor 500 mg t.i.d. Using strict evaluability and microbiologic/clinical response criteria 6 to 14 days post therapy, the following clinical cure rates, presumptive microbiologic eradication rates, and statistical outcomes were obtained:

 U.S. Community-Acquired Pneumonia Study Cefdinir vs Cefaclor

In a second controlled, investigator-blind study in adults and adolescents conducted primarily in Europe, cefdinir b.i.d. was compared with amoxicillin/clavulanate 500/125 mg t.i.d. Using strict evaluability and clinical response criteria 6 to 14 days post therapy, the following clinical cure rates, presumptive microbiologic eradication rates, and statistical outcomes were obtained:

European Community-Acquired Pneumonia Study Cefdinir vs Amoxicillin/Clavulanate

Streptococcal Pharyngitis /Tonsillitis

In four controlled studies conducted in the United States, cefdinir was compared with 10 days of penicillin in adult, adolescent, and pediatric patients. Two studies (one in adults and adolescents, the other in pediatric patients) compared 10 days of cefdinir q.d. or b.i.d. to penicillin 250 mg or 10 mg/kg q.i.d. Using strict evaluability and microbiologic/clinical response criteria 5 to 10 days post therapy, the following clinical cure rates, microbiologic eradication rates, and statistical outcomes were obtained:

Pharyngitis /Tonsillitis Studies Cefdinir (10 days ) vs Penicillin (10 days )

Two studies (one in adults and adolescents, the other in pediatric patients) compared 5 days of cefdinir b.i.d. to 10 days of penicillin 250 mg or 10 mg/kg q.i.d. Using strict evaluability and microbiologic/clinical response criteria 4 to 10 days post therapy, the following clinical cure rates, microbiologic eradication rates, and statistical outcomes were obtained:

Pharyngitis /Tonsillitis Studies Cefdinir (5 days ) vs Penicillin (10 days )

WARNINGS

BEFORE THERAPY WITH 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.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including cefdinir, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents 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 CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Interference with diagnostic tests

The development of a positive Coomb's Test associated with the use of cefdinir may interfere with cross matching of blood (see section 4.8).As a false negative result may occur in the ferricyanide test, it is recommended that either the glucose oxidase or hexokinase methods are used to determine blood/plasma glucose levels in patients receiving cefdinir.

PRECAUTIONS

General

Prescribing cefdinir in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

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

Excipients:

Denacif® contains sucrose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

(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 t½.

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 reports of reddish stools in patients receiving cefdinir. In many cases, patients were also receiving iron-containing products. 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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).

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 ≥100 mg/kg/day, and in rat offspring at ≥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.

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

No studies on the effects on the ability to drive and use machines have been performed. However, as this medicine may cause dizziness, patients should be warned to be cautious when driving or operating machinery.

Cefdinir Capsules (Adult and Adolescent Patients)

In clinical trials, 5093 adult and adolescent patients (3841 U.S. and 1252 non-U.S.) were treated with the recommended dose of cefdinir capsules (600 mg/day). Most adverse events were mild and self-limiting. No deaths or permanent disabilities were attributed to cefdinir. One hundred forty-seven of 5093 (3%) patients discontinued medication due to adverse events thought by the investigators to be possibly, probably, or definitely associated with cefdinir therapy. The discontinuations were primarily for gastrointestinal disturbances, usually diarrhea or nausea. Nineteen of 5093 (0.4%) patients were discontinued due to rash thought related to cefdinir administration.

In the U.S., the following adverse events were thought by investigators to be possibly, probably, or definitely related to cefdinir capsules in multiple-dose clinical trials (N=3841 cefdinir-treated patients):

Adverse Events Associated with Cefdinir Capsules U.S. Trials in Adult and Adolescent Patients (N=3841)*

* 1733 males, 2108 females

The  following  laboratory  value  changes  of  possible  clinical  significance,  irrespective  of relationship to therapy with cefdinir, were seen during clinical trials conducted in the U.S.:

Laboratory Value Changes Observed with Cefdinir Capsules U.S. Trials in Adult and

Patients (N=3841)

*N < 3841 for these parameters

Clinical Trials - Cefdinir for Oral Suspension (Pediatric Patients)

In clinical trials, 2289 pediatric patients (1783 U.S. and 506 non-U.S.) 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 U.S., 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):

ADVERSE EVENTS ASSOCIATED WITH CEFDINIR SUSPENSION U.S. TRIALS IN PEDIATRIC PATIENTS (N=1783)*

* 977 males, 806 females

† 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.

The  following  laboratory  value  changes  of  possible  clinical  significance,  irrespective  of relationship to therapy with cefdinir, were seen during clinical trials conducted in the U.S.:

LABORATORY VALUE CHANGES OF POSSIBLE CLINICAL SIGNIFICANCE OBSERVEDWITH CEFDINIR SUSPENSION U.S. TRIALS IN PEDIATRIC PATIENTS (N=1783)

*N=1387 for these parameters

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: shock, anaphylaxis with rare cases of fatality, facial and laryngeal edema, feeling of suffocation, serum sickness-like reactions, conjunctivitis, stomatitis,  Stevens-Johnson  syndrome,  toxic  epidermal  necrolysis,  exfoliative  dermatitis, erythema multiforme, erythema nodosum, acute  hepatitis, cholestasis, fulminant hepatitis, hepatic failure, jaundice, increased amylase, acute enterocolitis, bloody diarrhea, hemorrhagic colitis,  melena,  pseudomembranous  colitis,  pancytopenia,  granulocytopenia,  leucopenia, 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 effect(s):

•Saudi Arabia:

The National Pharmacovigilance and Drug Safety Center (NPC): Fax: +966-11-205-7662

Call NPC at +966-11-2038222, Exts: 2317-2356-2340.

Reporting hotline: 19999

E-mail: npc.drug@sfda.gov.sa Website: www.sfda.gov.sa/npc

•Other GCC States:

Please contact the relevant competent authority

To report any side effect(s):

•Saudi Arabia:

The National Pharmacovigilance and Drug Safety Center (NPC): Fax: +966-11-205-7662

Call NPC at +966-11-2038222, Exts: 2317-2356-2340.

Reporting hotline: 19999

E-mail: npc.drug@sfda.gov.sa Website: www.sfda.gov.sa/npc

•Other GCC States:

Please contact the relevant competent authority

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.

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.

Denacif®    contain  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 C14H13N5O5S2 and the molecular weight is 395.42.

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 Cmaxand 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 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 to 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 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.

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 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).

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.

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

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 aresult, 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 as described in INDICATIONS AND USAGE.

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

Haemophilusinfluenzae (including β-lactamase producing strains) Haemophilusparainfluenzae (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 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.

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(1) (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:*

These interpretive standards are applicable only to broth microdilution susceptibility tests with Haemophilus spp. using Haemophilus Test Medium (HTM). (1)

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

For Streptococcus spp:

Streptococcus pneumoniae that are susceptible to penicillin (MIC ≤ 0.06 mcg/mL), or streptococci other than S. pneumoniae that are susceptible to penicillin (MIC ≤ 0.12 mcg/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:

*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 procedure(2)requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 5 mcg 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 mcg cefdinir disk should be interpreted according to the following criteria:

For organisms other than Haemophilus spp. and Streptococcus spp:*

*Because certain strains of Citrobacter, Providencia, and Enterobacter spp. have beenreported 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:*

*These zone diameter standards are applicable only to tests with Haemophilusspp. using HTM.(2)

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

For Streptococcusspp:

Isolates of Streptococcus pneumoniae should be tested against a 1 mcg oxacillin disk. Isolates with oxacillin zone sizes ≥ 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 ≥ 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 mcg cefdinir disk should provide the following zone diameters in these laboratory quality control strains:

*This quality control range is applicable only to testing of H. influenzae ATCC 49766 using HTM.

Not applicable in Registed PIL in SFDA.

For capsules are microcrystalline cellulose, sodium lauryl sulphate, croscarmellose sodium, magnesium stearate.

For powder for oral suspension are Sucrose, methyl paraben (fine), xanthan gum, microcrystalline cellulose & Carboxymethyl cellulose sodium, citric acid.H2O (fine), tutti fruiti powder flavor, FD&C Red # 40, polysorbate 20, simethicone oil LVA, colloidal silicon dioxide, Isopropanol

Not applicable.

Store below 30°C.

After reconstitution, the suspension should be used within 14 days.

Denacif® 300 mg Capsules

Hard gelatin capsule with black opaque cap printed in white color with MD, Red opaque body printed in white color with Denacif 300, size zero, intended for oral use.

Pack size:

10 capsules in HDPE bottle.

Denacif® Powder for Oral Suspension

Dry state: peach to light pink granules with tutti fruity flavor Reconstituted powder: pink suspension with tutti fruity flavor.  

Pack size:

50 ml and 100 ml

No special requirements.