AMOXICILLIN AND CLAVULANATE POTASSIUM TABLETS USP, 500 mg/125 mg and 875 mg/125 mg, 2274, 2275, Rx only

/AMOXICILLIN AND CLAVULANATE POTASSIUM TABLETS USP, 500 mg/125 mg and 875 mg/125 mg, 2274, 2275, Rx only
AMOXICILLIN AND CLAVULANATE POTASSIUM TABLETS USP, 500 mg/125 mg and 875 mg/125 mg, 2274, 2275, Rx only2018-09-06T09:12:40+00:00

Prescription Drug Name:

AMOXICILLIN AND CLAVULANATE POTASSIUM TABLETS USP, 500 mg/125 mg and 875 mg/125 mg, 2274, 2275, Rx only

ID:

9404bff5-10f1-4359-8894-b6a5cb5ae198

Code:

34391-3

DESCRIPTION


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displayName: DESCRIPTION SECTION
FDA Article Code: 34089-3

Amoxicillin and clavulanate potassium 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. 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 has the following structural formula: C 16H19N3O5S·3H2O M.W. 419.46 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. Chemically, clavulanate potassium is potassium (Z)-(2R,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]-heptane-2-carboxylate, and has the following structural formula: C 8H8KNO5 M.W. 237.25 Each tablet contains 500 mg or 875 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt. Each amoxicillin and clavulanate potassium tablet contains 0.63 mEq 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. Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of amoxicillin. While amoxicillin and clavulanate potassium can be given without regard to meals, absorption of clavulanate potassium when taken with food is greater relative to the fasted state. In 1 study, the relative bioavailability of clavulanate was reduced when amoxicillin and clavulanate potassium was 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 was taken without regard to meals. Mean * amoxicillin and clavulanate potassium pharmacokinetic parameters are shown in the table below:

Dose and regimen AUC0-24 (mcg•hr/mL) Cmax (mcg/mL)
amoxicillin/clavulanate potassium amoxicillin (± S.D.) clavulanate potassium (± S.D.) amoxicillin (± S.D.) clavulanate potassium (± S.D.)
250/125 mg q8h 26.7 ± 4.56 12.6 ± 3.25 3.3 ± 1.12 1.5 ± 0.70
500/125 mg q12h 33.4 ± 6.76 8.6 ± 1.95 6.5 ± 1.41 1.8 ± 0.61
500/125 mg q8h 53.4 ± 8.87 15.7 ± 3.86 7.2 ± 2.26 2.4 ± 0.83
875/125 mg q12h 53.5 ± 12.31 10.2 ± 3.04 11.6 ± 2.78 2.2 ± 0.99
* Mean values of 14 normal volunteers (n = 15 for clavulanate potassium in the low-dose regimens). Peak concentrations occurred approximately 1.5 hours after the dose. Amoxicillin serum concentrations achieved with amoxicillin and clavulanate potassium 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 is 1.3 hours and that of clavulanic acid is 1.0 hour. 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 a single amoxicillin and clavulanate potassium tablet, 250 mg/125 mg or 500 mg/125 mg. Concurrent administration of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid. Neither component in amoxicillin and clavulanate potassium 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.

INDICATIONS AND USAGE


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

Amoxicillin and clavulanate potassium tablets are indicated in the treatment of infections caused by susceptible strains of the designated organisms in the conditions listed below:

CONTRAINDICATIONS


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displayName: CONTRAINDICATIONS SECTION
FDA Article Code: 34070-3

Amoxicillin and clavulanate potassium is 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


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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 HYPERSENSITIVITY 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 AND CLAVULANATE POTASSIUM, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OR OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, AMOXICILLIN AND 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 difficileassociated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including amoxicillin and clavulanate potassium, 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 should be used with caution in patients with evidence of hepatic dysfunction. Hepatic toxicity associated with the use of amoxicillin and clavulanate potassium 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


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displayName: ADVERSE REACTIONS SECTION
FDA Article Code: 34084-4

Amoxicillin and clavulanate potassium is 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. 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. The following adverse reactions have been reported for ampicillin-class antibiotics:

OVERDOSAGE


id: d4b8d4a6-17da-4a90-8762-ee3dd8e2384e
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, 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. (See DOSAGE AND ADMINISTRATION for recommended dosing for patients with impaired renal function.)

DOSAGE AND ADMINISTRATION


id: 5f827755-3bab-4eba-9c95-ff6181399424
displayName: DOSAGE & ADMINISTRATION SECTION
FDA Article Code: 34068-7

Since both amoxicillin and clavulanate potassium tablets USP, 250 mg/125 mg and 500 mg/125 mg, contain the same amount of clavulanic acid (125 mg, as the potassium salt), two amoxicillin and clavulanate potassium tablets USP, 250 mg/125 mg are not equivalent to one amoxicillin and clavulanate potassium tablet USP, 500 mg/125 mg. Therefore, two amoxicillin and clavulanate potassium tablets USP, 250 mg/125 mg should not be substituted for one amoxicillin and clavulanate potassium tablet USP, 500 mg/125 mg.

HOW SUPPLIED


id: 16cf9dc0-be78-41ad-8219-d6e4b776edd0
displayName: HOW SUPPLIED SECTION
FDA Article Code: 34069-5

Amoxicillin and clavulanate potassium tablets USP, 500 mg/125 mg are available as white, oblong-shaped, biconvex, film-coated tablets, debossed “93” on one side and “2274” on the other side. Each tablet contains 500 mg amoxicillin as the trihydrate and 125 mg of clavulanic acid as the potassium salt. They are available in bottles of 20. Amoxicillin and clavulanate potassium tablets USP, 875 mg/125 mg are available as white, capsule-shaped, biconvex, film-coated tablets, debossed “93” on one side and “22”, score, “75” on the other side. Each tablet contains 875 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt. They are available in bottles of 20. Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). Advise patients to keep in a closed container.

CLINICAL STUDIES


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displayName: CLINICAL STUDIES SECTION
FDA Article Code: 34092-7

Data from 2 pivotal studies in 1,191 patients treated for either lower respiratory tract infections or complicated urinary tract infections compared a regimen of 875 mg tablets of amoxicillin and clavulanate potassium q12h to 500 mg tablets of amoxicillin and clavulanate potassium dosed q8h (584 and 607 patients, respectively). Comparable efficacy was demonstrated between the q12h and q8h dosing regimens. There was no significant difference in the percentage of adverse events in each group. The most frequently reported adverse event was diarrhea; incidence rates were similar for the 875 mg q12h and 500 mg q8h dosing regimens (14.9% and 14.3%, respectively); however, there was a statistically significant difference ( p < 0.05) in rates of severe diarrhea or withdrawals with diarrhea between the regimens: 1.0% for 875 mg q12h versus 2.5% for the 500 mg q8h dosing. In 1 of these pivotal studies, 629 patients with either pyelonephritis or a complicated urinary tract infection (i.e., patients with abnormalities of the urinary tract that predispose to relapse of bacteriuria following eradication) were randomized to receive either 875 mg amoxicillin and clavulanate potassium tablets q12h or 500 mg amoxicillin and clavulanate potassium tablets q8h in the following distribution:


875 mg q12h

500 mg q8h
Pyelonephritis 173 patients 188 patients
Complicated UTI 135 patients 133 patients
Total patients 308 321
The number of bacteriologically evaluable patients was comparable between the 2 dosing regimens. Amoxicillin and clavulanate potassium produced comparable bacteriological success rates in patients assessed 2 to 4 days immediately following end of therapy. The bacteriologic efficacy rates were comparable at 1 of the follow-up visits (5 to 9 days post-therapy) and at a late post-therapy visit (in the majority of cases, this was 2 to 4 weeks post-therapy), as seen in the table below:

875 mg q12h

500 mg q8h
2 to 4 days 81%, n = 58 80%, n = 54
5 to 9 days 58.5%, n = 41 51.9%, n = 52
2 to 4 weeks 52.5%, n = 101 54.8%, n = 104
As noted before, though there was no significant difference in the percentage of adverse events in each group, there was a statistically significant difference in rates of severe diarrhea or withdrawals with diarrhea between the regimens.

REFERENCES


id: 0e805764-d3b3-451c-8af6-d0cf8245ea05
displayName: REFERENCES SECTION
FDA Article Code: 34093-5

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, December 1993.
National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests – Fifth Edition. Approved Standard NCCLS Document M2-A5, Vol. 13, No. 24. NCCLS, Villanova, PA, December 1993.
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: f9b35b42-1e73-4dda-85ea-ae865df5d9f8
displayName: PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FDA Article Code: 51945-4

Principal Display Panel


id: 5868aa97-d1d8-4759-9650-e62dc0107aed
displayName: PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FDA Article Code: 51945-4