CEFDINIR

Cefdinir for oral suspension, USP contains the active ingredient cefdinir USP, 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 USP 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 molecular formula is C 14 H 13 N 5 O 5 S 2 and the molecular weight is 395.42. Cefdinir has the structural formula shown below: Cefdinir for oral suspension, USP after reconstitution, contains 125 mg cefdinir USP per 5 mL or 250 mg cefdinir USP per 5 mL and the following inactive ingredients: sucrose, sodium benzoate, colloidal silicone dioxide, xanthan gum, guar gum, citric acid (anhydrous), sodium citrate (dihydrate), strawberry flavour, fresh cream flavour and magnesium stearate. Chemical Structure

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. Cefdinir for oral suspension 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 pneumoniae (penicillin-susceptible strains only), and Moraxella catarrhalis (including β-lactamase producing strains) (see CLINICAL STUDIES ). Acute Exacerbations of Chronic Bronchitis caused by Haemophilus influenzae (including β-lactamase producing strains), Haemophilus parainfluenzae (including β-lactamase producing strains), Streptococcus pneumoniae (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, see PRECAUTIONS, Pediatric Use and DOSAGE AND ADMINISTRATION . 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 . 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) 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, cefdinir for oral suspension should be administered twice daily in this infection. Cefdinir for oral suspension may be administered without regard to meals. Pediatric Patients (Age 6 Months Through 12 Years) Type of Infection Dosage Duration Acute Bacterial Otitis Media 7 mg/kg q12h or 14 mg/kg q24h 5 to 10 days 10 days Acute Maxillary Sinusitis 7 mg/kg q12h or 14 mg/kg q24h 10 days 10 days Pharyngitis/Tonsillitis 7 mg/kg q12h or 14 mg/kg q24h 5 to 10 days 10 days Uncomplicated Skin and Skin Structure Infections 7 mg/kg q12h 10 days CEFDINIR FOR ORAL SUSPENSION PEDIATRIC DOSAGE CHART a Pediatric patients who weigh ≥ 43 kg should receive the maximum daily dose of 600 mg. Weight 125 mg/5 mL 250 mg/5 mL 9 kg/20 lbs 2.5 mL q12h or 5 mL q24h Use 125 mg/5 mL product 18 kg/40 lbs 5 mL q12h or 10 mL q24h 2.5 mL q12h or 5 mL q24h 27 kg/60 lbs 7.5 mL q12h or 15 mL q24h 3.75 mL q12h or 7.5 mL q24h 36 kg/80 lbs 10 mL q12h or 20 mL q24h 5 mL q12h or 10 mL q24h ≥ 43 kg a /95 lbs 12 mL q12h or 24 mL q24h 6 mL q12h or 12 mL q24h Patients With Renal Insufficiency For adult patients with creatinine clearance <30 mL/min, the dose of cefdinir 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 (CL cr ) in adult patients. For estimates to be valid, serum creatinine levels should reflect steady-state levels of renal function. Males: CL cr = (weight) (140 – age) (72) (serum creatinine) Females: CL cr = 0.85 x above value where creatinine clearance is in mL/min, age is in years, weight is in kilograms, and serum creatinine is in mg/dL. 1 The following formula may be used to estimate creatinine clearance in pediatric patients: CL cr = K x body length or height serum creatinine where K=0.55 for pediatric patients older than 1 year 2 and 0.45 for infants (up to 1 year) 3 . In the above equation, creatinine clearance is in mL/min/1.73 m 2 , 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 m 2 , 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 7 mg/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 Final Concentration Final Volume (mL) Amount of Water Directions 125 mg/5 mL 60 100 38 mL 63 mL Tap bottle to loosen powder, then add water in 2 portions. Shake well after each aliquot. 250 mg/5 mL 60 100 38 mL 63 mL Tap bottle to loosen powder, then add water in 2 portions. Shake well after each aliquot. After mixing, the suspension can be stored at room temperature (25°C/77°F). The container should be kept tightly closed, and the suspension should be shaken well before each administration. The suspension may be used for 10 days, after which any unused portion must be discarded.

Cefdinir is contraindicated in patients with known allergy to the cephalosporin class of antibiotics.

ADVERSE EVENTS Clinical Trials - 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) a a 1733 males, 2108 females Incidence ≥1% Diarrhea 15% Vaginal moniliasis 4% of women Nausea 3% Headache 2% Abdominal pain 1% Vaginitis 1% of women Incidence <1% but >0.1% Rash 0.9% Dyspepsia 0.7% Flatulence 0.7% Vomiting 0.7% Abnormal stools 0.3% Anorexia 0.3% Constipation 0.3% Dizziness 0.3% Dry mouth 0.3% Asthenia 0.2% Insomnia 0.2% Leukorrhea 0.2% of women Moniliasis 0.2% Pruritus 0.2% Somnolence 0.2% 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 ADOLESCENT PATIENTS (N = 3841) a N <3841 for these parameters Incidence ≥1% ↑Urine leukocytes 2% ↑Urine protein 2% ↑Gamma-glutamyltransferase a 1% ↓Lymphocytes, ↑Lymphocytes 1%, 0.2% ↑Microhematuria 1% Incidence <1% but >0.1% ↑Glucose a 0.9% ↑Urine glucose 0.9% ↑White blood cells, ↓White blood cells 0.9%, 0.7% ↑Alanine aminotransferase (ALT) 0.7% ↑Eosinophils 0.7% ↑Urine specific gravity, ↓Urine specific gravity a 0.6%, 0.2% ↓Bicarbonate a 0.6% ↑Phosphorus, ↓Phosphorus a 0.6%, 0.3% ↑Aspartate aminotransferase (AST) 0.4% ↑Alkaline phosphatase 0.3% ↑Blood urea nitrogen (BUN) 0.3% ↓Hemoglobin 0.3% ↑Polymorphonuclear neutrophils (PMNs), ↓PMNs 0.3%, 0.2% ↑Bilirubin 0.2% ↑Lactate dehydrogenase a 0.2% ↑Platelets 0.2% ↑Potassium a 0.2% ↑Urine pH a 0.2% 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) a a 977 males, 806 females b Laboratory changes were occasionally reported as adverse events. Incidence ≥ 1% Diarrhea 8% Rash 3% Vomiting 1% Incidence <1% but >0.1% Cutaneous moniliasis 0.9% Abdominal pain 0.8% Leukopenia b 0.3% Vaginal moniliasis 0.3% of girls Vaginitis 0.3% of girls Abnormal stools 0.2% Dyspepsia 0.2% Hyperkinesia 0.2% Increased AST b 0.2% Maculopapular rash 0.2% Nausea 0.2% 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 OBSERVED WITH CEFDINIR SUSPENSION U.S. TRIALS IN PEDIATRIC PATIENTS (N = 1783) a N = 1387 for these parameters Incidence ≥1% ↑Lymphocytes, ↓Lymphocytes 2%, 0.8% ↑Alkaline phosphatase 1% ↓Bicarbonate a 1% ↑Eosinophils 1% ↑Lactate dehydrogenase 1% ↑Platelets 1% ↑PMNs, ↓PMNs 1%, 1% ↑Urine protein 1% Incidence <1% but >0.1% ↑Phosphorus, ↓Phosphorus 0.9%, 0.4% ↑Urine pH 0.8% ↓White blood cells, ↑White blood cells 0.7%, 0.3% ↓Calcium a 0.5% ↓Hemoglobin 0.5% ↑Urine leukocytes 0.5% ↑Monocytes 0.4% ↑AST 0.3% ↑Potassium a 0.3% ↑Urine specific gravity, ↓Urine specific gravity 0.3%, 0.1% ↓Hematocrit a 0.2% Postmarketing 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, 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 (see WARNINGS ). Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced (see DOSAGE AND ADMINISTRATION and OVERDOSAGE ). If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.

Antacids: ( aluminum- or magnesium-containing ) Concomitant administration of 300 mg cefdinir capsules with 30 mL Maalox ® TC suspension reduces the rate (C max ) and extent (AUC) of absorption by approximately 40%. Time to reach C max 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 t ½ . Iron Supplements and Foods Fortified With Iron Concomitant administration of cefdinir with a therapeutic iron supplement containing 60 mg of elemental iron (as FeSO 4 ) 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.