Amoxicillin and Clavulanate Potassium, Powder for Oral Suspension, USP and Chewable Tablets, USP

/Amoxicillin and Clavulanate Potassium, Powder for Oral Suspension, USP and Chewable Tablets, USP
Amoxicillin and Clavulanate Potassium, Powder for Oral Suspension, USP and Chewable Tablets, USP2018-09-06T09:12:40+00:00

Prescription Drug Name:

Amoxicillin and Clavulanate Potassium, Powder for Oral Suspension, USP and Chewable Tablets, USP

ID:

2970fe7e-9e1f-47aa-85ad-663ee15c7e06

Code:

34391-3

DESCRIPTION


id: 98385fa1-4e74-476d-a3f5-ebf61edd3624
displayName: DESCRIPTION SECTION
FDA Article Code: 34089-3

Amoxicillin and clavulanate potassium for oral suspension and chewable tablets are an oral antibacterial combination consisting of the semisynthetic antibiotic amoxicillin and the β-lactamase inhibitor, clavulanate potassium (the potassium salt of clavulanic acid). Amoxicillin is an analog of ampicillin, derived from the basic penicillin nucleus, 6-aminopenicillanic acid. The amoxicillin molecular formula is C16H19N3O5S•3H2O and the molecular weight is 419.46. Chemically, amoxicillin is (2S,5R,6R)- 6-((R)-(-)-2-Amino-2-(p-hydroxyphenyl) acetamido]-3,3-dimethyl- 7-oxo-4-thia-1-azabicyclo(3.2.0) heptane-2-carboxylic acid trihydrate and may be represented structurally as: Clavulanic acid is produced by the fermentation of Streptomyces clavuligerus. It is a β-lactam structurally related to the penicillins and possesses the ability to inactivate a wide variety of β-lactamases by blocking the active sites of these enzymes. Clavulanic acid is particularly active against the clinically important plasmid mediated β-lactamases frequently responsible for transferred drug resistance to penicillins and cephalosporins. The clavulanate potassium molecular formula is C8H8KNO5 and the molecular weight is 237.25. Chemically clavulanate potassium is potassium (Z)-(2R,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]-heptane-2-carboxylate and may be represented structurally as: Each chewable tablet and each teaspoon (5 mL) of reconstituted oral suspension contains 200 mg or 400 mg amoxicillin as the trihydrate and 28.5 or 57 mg clavulanic acid as the potassium salt. Each 200 mg/28.5 mg chewable tablet and each 5 mL of reconstituted amoxicillin and clavulanate potassium 200 mg/28.5 mg oral suspension contains 0.14 mEq potassium. Each 400 mg/57 mg chewable tablet and each 5 mL of reconstituted 400 mg/57 mg oral suspension contains 0.29 mEq of potassium.

CLINICAL PHARMACOLOGY


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displayName: CLINICAL PHARMACOLOGY SECTION
FDA Article Code: 34090-1

Amoxicillin and clavulanate potassium are well absorbed from the gastrointestinal tract after oral administration of amoxicillin and clavulanate potassium for oral suspension and chewable tablets. Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of amoxicillin. While amoxicillin and clavulanate potassium for oral suspension and chewable tablets can be given without regard to meals, absorption of clavulanate potassium when taken with food is greater relative to the fasted state. In one study, the relative bioavailability of clavulanate was reduced when amoxicillin and clavulanate potassium for oral suspension and chewable tablets were dosed at 30 and 150 minutes after the start of a high fat breakfast. The safety and efficacy of amoxicillin and clavulanate potassium have been established in clinical trials where amoxicillin and clavulanate potassium for oral suspension and chewable tablets were taken without regard to meals. Oral administration of single doses of 400 mg/57 mg amoxicillin and clavulanate potassium chewable tablets and 400 mg/57 mg per 5 mL suspension to 28 adult volunteers yielded comparable pharmacokinetic data:

DoseAdministered at the start of a light meal.
AUC0-∞ (mcg.hr./mL) Cmax (mcg/mL)Mean values of 28 normal volunteers. Peak concentrations occurred approximately 1 hour after the dose.
(amoxicillin and clavulanate potassium) amoxicillin (± S.D.) clavulanate potassium (± S.D.) amoxicillin (± S.D.) clavulanate potassium (± S.D.)
400 mg/57 mg (5 mL ofsuspension) 17.29 ± 2.28 2.34 ± 0.94 6.94 ± 1.24 1.10 ± 0.42
400 mg/57 mg (one chewabletablet) 17.24 ± 2.64 2.17 ± 0.73 6.67 ± 1.37 1.03 ± 0.33
Oral administration of 5 mL of amoxicillin and clavulanate potassium 250 mg/62.5 mg suspension or the equivalent dose of 10 mL amoxicillin and clavulanate potassium 125 mg/31.25 mg suspension provides average peak serum concentrations approximately 1 hour after dosing of 6.9 mcg/mL for amoxicillin and 1.6 mcg/mL for clavulanic acid. The areas under the serum concentration curves obtained during the first 4 hours after dosing were 12.6 mcg.hr./mL for amoxicillin and 2.9 mcg.hr./mL for clavulanic acid when 5 mL of amoxicillin and clavulanate potassium 250 mg/62.5 mg suspension or equivalent dose of 10 mL of amoxicillin and clavulanate potassium 125 mg/31.25 mg suspension was administered to adult volunteers. One amoxicillin and clavulanate potassium 250 mg/62.5 mg chewable tablet or 2 amoxicillin and clavulanate potassium 125 mg/31.25 mg chewable tablets are equivalent to 5 mL of amoxicillin and clavulanate potassium 250 mg/62.5 mg suspension and provide similar serum levels of amoxicillin and clavulanic acid. Amoxicillin serum concentrations achieved with amoxicillin and clavulanate potassium for oral suspension and chewable tablets are similar to those produced by the oral administration of equivalent doses of amoxicillin alone. The half-life of amoxicillin after the oral administration of amoxicillin and clavulanate potassium for oral suspension and chewable tablets is 1.3 hours and that of clavulanic acid is 1.0 hour. Time above the minimum inhibitory concentration of 1.0 mcg/mL for amoxicillin has been shown to be similar after corresponding q12h and q8h dosing regimens of amoxicillin and clavulanate potassium for oral suspension and chewable tablets in adults and children. Approximately 50% to 70% of the amoxicillin and approximately 25% to 40% of the clavulanic acid are excreted unchanged in urine during the first 6 hours after administration of 10 mL of amoxicillin and clavulanate potassium 250 mg/62.5 mg suspension. Concurrent administration of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid. Neither component in amoxicillin and clavulanate potassium for oral suspension and chewable tablets is highly protein-bound; clavulanic acid has been found to be approximately 25% bound to human serum and amoxicillin approximately 18% bound. Amoxicillin diffuses readily into most body tissues and fluids with the exception of the brain and spinal fluid. The results of experiments involving the administration of clavulanic acid to animals suggest that this compound, like amoxicillin, is well distributed in body tissues. Two hours after oral administration of a single 35 mg/kg dose of amoxicillin and clavulanate potassium suspension to fasting children, average concentrations of 3 mcg/mL of amoxicillin and 0.5 mcg/mL of clavulanic acid were detected in middle ear effusions.

INDICATIONS AND USAGE


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displayName: INDICATIONS & USAGE SECTION
FDA Article Code: 34067-9

Amoxicillin and clavulanate potassium for oral suspension and chewable tablets are indicated in the treatment of infections caused by susceptible strains of the designated organisms in the conditions listed below: Lower Respiratory Tract Infections – caused by β-lactamase-producing strains of H. influenzae and M. catarrhalis. Otitis Media – caused by β-lactamase-producing strains of H. influenzae and M. catarrhalis. Sinusitis – caused by β-lactamase-producing strains of H. influenzae and M. catarrhalis. Skin and Skin Structure Infections – caused by β-lactamase-producing strains of S. aureus, E. coli and Klebsiella spp. Urinary Tract Infections – caused by β-lactamase-producing strains of E. coli, Klebsiella spp. and Enterobacter spp. While amoxicillin and clavulanate potassium for oral suspension and chewable tablets are indicated only for the conditions listed above, infections caused by ampicillin-susceptible organisms are also amenable to amoxicillin and clavulanate potassium for oral suspension and chewable tablets treatment due to its amoxicillin content. Therefore, mixed infections caused by ampicillin-susceptible organisms and β-lactamase-producing organisms susceptible to amoxicillin and clavulanate potassium for oral suspension and chewable tablets should not require the addition of another antibiotic. Because amoxicillin has greater in-vitro activity against S. pneumoniae than does ampicillin or penicillin, the majority of S. pneumoniae strains with intermediate susceptibility to ampicillin or penicillin are fully susceptible to amoxicillin and amoxicillin and clavulanate potassium for oral suspension and chewable tablets. (See Microbiology .) To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin and clavulanate potassium for oral suspension and chewable tablets and other antibacterial drugs, amoxicillin and clavulanate potassium for oral suspension and chewable tablets 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. Bacteriological studies, to determine the causative organisms and their susceptibility to amoxicillin and clavulanate potassium for oral suspension and chewable tablets, should be performed together with any indicated surgical procedures.

CONTRAINDICATIONS


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displayName: CONTRAINDICATIONS SECTION
FDA Article Code: 34070-3

Amoxicillin and clavulanate potassium for oral suspension and chewable tablets are contraindicated in patients with a history of allergic reactions to any penicillin. It is also contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with amoxicillin and clavulanate potassium.

WARNINGS


id: 3a65cbef-e64c-445d-9ab1-09cde75e3bf7
displayName: WARNINGS SECTION
FDA Article Code: 34071-1

SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC) REACTIONS HAVE BEEN REPORTED IN PATIENTS ON PENICILLIN THERAPY. THESE REACTIONS ARE MORE LIKELY TO OCCUR IN INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPER-SENSITIVITY AND/OR A HISTORY OF SENSITIVITY TO MULTIPLE ALLERGENS. THERE HAVE BEEN REPORTS OF INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY WHO HAVE EXPERIENCED SEVERE REACTIONS WHEN TREATED WITH CEPHALOSPORINS. BEFORE INITIATING THERAPY WITH AMOXICILLIN/CLAVULANATE POTASSIUM, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS OR OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, AMOXICILLIN/CLAVULANATE POTASSIUM SHOULD BE DISCONTINUED AND THE APPROPRIATE THERAPY INSTITUTED. SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS AND AIRWAY MANAGEMENT, INCLUDING INTUBATION, SHOULD ALSO BE ADMINISTERED AS INDICATED. Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including amoxicillin and clavulanate potassium for oral suspension and chewable tablets, 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. Amoxicillin and clavulanate potassium for oral suspension and chewable tablets should be used with caution in patients with evidence of hepatic dysfunction. Hepatic toxicity associated with the use of amoxicillin and clavulanate potassium for oral suspension and chewable tablets is usually reversible. On rare occasions, deaths have been reported (less than 1 death reported per estimated 4 million prescriptions worldwide). These have generally been cases associated with serious underlying diseases or concomitant medications. (See CONTRAINDICATIONS and ADVERSE REACTIONS-Liver .)

ADVERSE REACTIONS


id: 07f44e94-c988-4a7d-b9d3-ef0f469decf6
displayName: ADVERSE REACTIONS SECTION
FDA Article Code: 34084-4

Amoxicillin and clavulanate potassium for oral suspension and chewable tablets are generally well tolerated. The majority of side effects observed in clinical trials were of a mild and transient nature and less than 3% of patients discontinued therapy because of drug-related side effects. From the original premarketing studies, where both pediatric and adult patients were enrolled, the most frequently reported adverse effects were diarrhea/loose stools (9%), nausea (3%), skin rashes and urticaria (3%), vomiting (1%) and vaginitis (1%). The overall incidence of side effects, and in particular diarrhea, increased with the higher recommended dose. Other less frequently reported reactions include: abdominal discomfort, flatulence and headache. In pediatric patients (aged 2 months to 12 years), one U.S./Canadian clinical trial was conducted which compared amoxicillin and clavulanate potassium for oral suspension and chewable tablets 45/6.4 mg/kg/day (divided q12h) for 10 days versus amoxicillin and clavulanate potassium for oral suspension and chewable tablets 40/10 mg/kg/day (divided q8h) for 10 days in the treatment of acute otitis media. A total of 575 patients were enrolled, and only the suspension formulations were used in this trial. Overall, the adverse event profile seen was comparable to that noted above. However, there were differences in the rates of diarrhea, skin rashes/urticaria, and diaper area rashes. (See CLINICAL STUDIES .) The following adverse reactions have been reported for ampicillin class antibiotics:

OVERDOSAGE


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displayName: OVERDOSAGE SECTION
FDA Article Code: 34088-5

Following overdosage, patients have experienced primarily gastrointestinal symptoms including stomach and abdominal pain, vomiting, and diarrhea. Rash, hyperactivity, or drowsiness have also been observed in a small number of patients. In the case of overdosage, discontinue amoxicillin and clavulanate potassium for oral suspension and chewable tablets, treat symptomatically, and institute supportive measures as required. If the overdosage is very recent and there is no contraindication, an attempt at emesis or other means of removal of drug from the stomach may be performed. A prospective study of 51 pediatric patients at a poison center suggested that overdosages of less than 250 mg/kg of amoxicillin are not associated with significant clinical symptoms and do not require gastric emptying.3 Interstitial nephritis resulting in oliguric renal failure has been reported in a small number of patients after overdosage with amoxicillin. Crystalluria, in some cases leading to renal failure, has also been reported after amoxicillin overdosage in adult and pediatric patients. In case of overdosage, adequate fluid intake and diuresis should be maintained to reduce the risk of amoxicillin crystalluria. Renal impairment appears to be reversible with cessation of drug administration. High blood levels may occur more readily in patients with impaired renal function because of decreased renal clearance of both amoxicillin and clavulanate. Both amoxicillin and clavulanate are removed from the circulation by hemodialysis.

DOSAGE AND ADMINISTRATION


id: 79e99e39-87da-4b44-b949-26230a2a5776
displayName: DOSAGE & ADMINISTRATION SECTION
FDA Article Code: 34068-7

All recommended dosages for Amoxicillin and Clavulanate Potassium for Oral Suspension and Chewable Tablets are included in this section for informational purposes only. Some of the dosages may not be obtainable with the 400 mg/57mg per 5 mL and 200 mg/28.5 mg per 5 mL strengths of oral suspension or the 400 mg/57 mg and 200 mg/28.5 mg strengths of chewable tablets.

HOW SUPPLIED


id: 18916af0-ecc6-43d1-8748-5d2e001857e8
displayName: HOW SUPPLIED SECTION
FDA Article Code: 34069-5

Amoxicillin and clavulanate potassium for oral suspension, USP is supplied as a dry white powder containing: Amoxicillin and Clavulanate Potassium 200 mg/28.5 mg per 5 mL: Each 5 mL of reconstituted carmel-orange-raspberry flavored suspension contains 200 mg amoxicillin and 28.5 mg clavulanic acid as the potassium salt. NDC 21695-0767-50 – 50 mL bottle

CLINICAL STUDIES


id: a2f9d883-0b56-4fea-a7fd-6672032db445
displayName: CLINICAL STUDIES SECTION
FDA Article Code: 34092-7

In pediatric patients (aged 2 months to 12 years), one U.S./Canadian clinical trial was conducted which compared amoxicillin and clavulanate potassium for oral suspension and chewable tablets 45/6.4 mg/kg/day (divided q12h) for 10 days versus amoxicillin and clavulanate potassium for oral suspension and chewable tablets 40/10 mg/kg/day (divided q8h) for 10 days in the treatment of acute otitis media. Only the suspension formulations were used in this trial. A total of 575 patients were enrolled, with an even distribution among the two treatment groups and a comparable number of patients were evaluable (i.e., ≥84%) per treatment group. Strict otitis media-specific criteria were required for eligibility and a strong correlation was found at the end of therapy and follow-up between these criteria and physician assessment of clinical response. The clinical efficacy rates at the end of therapy visit (defined as 2-4 days after the completion of therapy) and at the follow-up visit (defined as 22-28 days post-completion of therapy) were compa-rable for the two treatment groups, with the following cure rates obtained for the evaluable patients: At end of therapy, 87.2% (n=265) and 82.3% (n=260) for 45 mg/kg/day q12h and 40 mg/kg/day q8h, respectively. At follow-up, 67.1% (n=249) and 68.7% (n=243) for 45 mg/kg/day q12h and 40 mg/kg/day q8h, respectively. The incidence of diarrhea### was significantly lower in patients in the q12h treatment group compared to patients who received the q8h regimen (14.3% and 34.3%, respectively). In addition, the number of patients with either severe diarrhea or who were withdrawn with diarrhea was significantly lower in the q12h treatment group (3.1% and 7.6% for the q12h/10 day and q8h/10 day, respectively). In the q12h treatment group, 3 patients (1.0%) were withdrawn with an allergic reaction, while 1 patient (0.3%) in the q8h group was withdrawn for this reason. The number of patients with a candidal infection of the diaper area was 3.8% and 6.2% for the q12h and q8h groups, respectively. It is not known if the finding of a statistically significant reduction in diarrhea with the oral suspensions dosed q12h, versus suspensions dosed q8h, can be extrapolated to the chewable tablets. The presence of mannitol in the chewable tablets may contribute to a different diarrhea profile. The q12h oral suspensions are sweetened with aspartame only. ### Diarrhea was defined as either: (a) three or more watery or four or more loose/watery stools in one day; OR (b) two watery stools per day or three loose/watery stools per day for two consecutive days.

REFERENCES


id: 537aecad-2111-4e46-a079-a8b55cfb7917
displayName: REFERENCES SECTION
FDA Article Code: 34093-5

1. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically – Third Edition. Approved Standard NCCLS Document M7-A3, Vol. 13, No. 25. NCCLS, Villanova, PA, Dec. 1993. 2. National Committee for Clinical Laboratory Standards. Performance Standard for Antimicrobial Disk Susceptibility Tests – Fifth Edition. Approved Standard NCCLS Document M2- A5, Vol. 13, No. 24. NCCLS, Villanova, PA, Dec. 1993. 3. Swanson-Biearman B, Dean BS, Lopez G, Krenzelok EP. The effects of penicillin and cephalosporin ingestions in children less than six years of age. Vet Hum Toxicol 1988;30:66-67. CLINITEST® is a registered trademark of Miles, Inc. CLINISTIX® is a registered trademark of Bayer Corporation.

Principal Display Panel


id: 53738297-e675-49ae-9d34-9cde7600c049
displayName: PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FDA Article Code: 51945-4