Amoxicillin and Clavulanate Potassium Tablets, USP

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. 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 has the following structural formula: 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 has the following structural formula: Each film coated tablet for oral administration contains 250 mg, 500 mg, or 875 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt. Each Amoxicillin and Clavulanate Potassium Tablet 250 mg/125 mg, 500 mg/125 mg, or 875 mg/125 mg contains 0.63 mEq potassium. Inactive Ingredients: colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, talc, titanium dioxide and triethyl citrate. In addition, the 250 mg/125 mg tablet contains cetyl alcohol and sodium lauryl sulphate; the 500 mg/125 mg tablet contains ethylcellulose aqueous dispersion; and the 875 mg/125 mg tablet contains crospovidone and ethylcellulose aqueous dispersion.

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 Tablets. Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of amoxicillin. While Amoxicillin and Clavulanate Potassium Tablets 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 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 Tablets have been established in clinical trials where Amoxicillin and Clavulanate Potassium Tablets were taken without regard to meals.

MeanMean 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 and clavulanate potassium pharmacokinetic parameters are shown in the table below:
DoseAdministered at the start of a light meal. 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 mg/125 mg q8h	26.7 ± 4.56	12.6 ± 3.25	3.3 ± 1.12	1.5 ± 0.70
500 mg/125 mg q12h	33.4 ± 6.76	8.6 ± 1.95	6.5 ± 1.41	1.8 ± 0.61
500 mg/125 mg q8h	53.4 ± 8.87	15.7 ± 3.86	7.2 ± 2.26	2.4 ± 0.83
875 mg/125 mg q12h	53.5 ± 12.31	10.2 ± 3.04	11.6 ± 2.78	2.2 ± 0.99

Amoxicillin serum concentrations achieved with Amoxicillin and Clavulanate Potassium 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 Tablets is 1.3 hours and that of clavulanic acid is 1 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 250 mg/125 mg or 500 mg/125 mg Tablet. Concurrent administration of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid. Neither component in Amoxicillin and Clavulanate Potassium 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.

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: 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 Tablets are indicated only for the conditions listed above, infections caused by ampicillin-susceptible organisms are also amenable to treatment with Amoxicillin and Clavulanate Potassium Tablets due to its amoxicillin content; therefore, mixed infections caused by ampicillin-susceptible organisms and β-lactamase-producing organisms susceptible to Amoxicillin and Clavulanate Potassium 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 Tablets. (See Microbiology.) To reduce the development of drug-resistant bacteria and maintain the effectiveness of Amoxicillin and Clavulanate Potassium Tablets and other antibacterial drugs, Amoxicillin and Clavulanate Potassium 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 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 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 Tablets.

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 TABLETS, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OR OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, AMOXICILLIN AND CLAVULANATE POTASSIUM TABLETS 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. Pseudomembranous colitis has been reported with nearly all antibacterial agents, including Amoxicillin and Clavulanate Potassium Tablets, and has ranged in severity from mild to life-threatening; therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of “antibiotic-associated colitis.” After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against C. difficile colitis. Amoxicillin and Clavulanate Potassium Tablets should be used with caution in patients with evidence of hepatic dysfunction. Hepatic toxicity associated with the use of Amoxicillin and Clavulanate Potassium 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

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

Amoxicillin and Clavulanate Potassium 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. 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

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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 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 emptying³. 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

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displayName: DOSAGE & ADMINISTRATION SECTION
FDA Article Code: 34068-7

Since both the Amoxicillin and Clavulanate Potassium 250 mg/125 mg and 500 mg/125 mg Tablets contain the same amount of clavulanic acid (125 mg, as the potassium salt), two Amoxicillin and Clavulanate Potassium 250 mg/125 mg Tablets are not equivalent to one Amoxicillin and Clavulanate Potassium 500 mg/125 mg Tablet; therefore, two Amoxicillin and Clavulanate Potassium 250 mg/125 mg Tablets should not be substituted for one Amoxicillin and Clavulanate Potassium 500 mg/125 mg Tablet.

HOW SUPPLIED

id: afcc6d6d-ecd6-4912-8a05-e548d92b2e32
displayName: HOW SUPPLIED SECTION
FDA Article Code: 34069-5

Amoxicillin and Clavulanate Potassium Tablets, USP, 250 mg/125 mg: Each film coated tablet, for oral administration, is white, capsule-shaped, debossed GGN5 on one side and plain on the reverse side, and contains 250 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt. Amoxicillin and Clavulanate Potassium Tablets, USP, 500 mg/125 mg: Each film coated tablet, for oral administration, is white, oval-shaped, debossed GGN6 on one side and plain on the reverse side, and contains 500 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt. Amoxicillin and Clavulanate Potassium Tablets, USP, 875 mg/125 mg: Each film coated tablet, for oral administration, is white, capsule-shaped, scored and debossed GGN7 on one side and scored on the reverse side, and contains 875 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt. Amoxicillin and Clavulanate Potassium are also available as: Amoxicillin and Clavulanate Potassium for Oral Suspension, USP, 200 mg/28.5 mg/5 mL: as a dry, white powder. Each 5 mL of reconstituted orange-flavored suspension contains 200 mg amoxicillin as the trihydrate and 28.5 mg clavulanic acid as the potassium salt. Amoxicillin and Clavulanate Potassium for Oral Suspension, USP, 400 mg/57 mg/5 mL: as a dry, white powder. Each 5 mL of reconstituted orange-flavored suspension contains 400 mg amoxicillin as the trihydrate and 57 mg clavulanic acid as the potassium salt. Amoxicillin and Clavulanate Potassium Tablets, USP, (Chewable) 200 mg/28.5 mg: Each chewable tablet is round, pink, cherry-banana flavored, embossed GGN2 on one side and plain on the reverse side, and contains 200 mg amoxicillin as the trihydrate and 28.5 mg clavulanic acid as the potassium salt. Amoxicillin and Clavulanate Potassium Tablets, USP, (Chewable) 400 mg/57 mg: Each chewable tablet is round, pink, cherry-banana flavored, embossed GGN4 on one side and plain on the reverse side, and contains 400 mg amoxicillin as the trihydrate and 57 mg clavulanic acid as the potassium salt. They are supplied by State of Florida DOH Central Pharmacy as follows:

NDC	Strength	Quantity/Form	Color	Source Prod. Code
53808-0759-1	250 mg / 125 mg	30 Dose Packs in a Carton	WHITE	0781-1874

CLINICAL STUDIES

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

Data from two pivotal studies in 1,191 patients treated for either lower respiratory tract infections or complicated urinary tract infections compared a regimen of 875 mg/125 mg Amoxicillin and Clavulanate Potassium Tablets q12h to 500 mg/125 mg Amoxicillin and Clavulanate Potassium Tablets 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/125 mg q12h and 500 mg/125 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% for 875 mg/125 mg q12h dosing versus 2.5% for the 500 mg/125 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/125 mg Amoxicillin and Clavulanate Potassium Tablets q12h or 500 mg/125 mg Amoxicillin and Clavulanate Potassium Tablets q8h in the following distribution:

	875 mg/125 mg q12h	500 mg/125 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 two dosing regimens. Amoxicillin and Clavulanate Potassium Tablets produced comparable bacteriological success rates in patients assessed 2 to 4 days immediately following end of therapy. The bacteriological efficacy rates were comparable at one 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/125 mg q12h	500 mg/125 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 sinificant difference in rates of severe diarrhea or withdrawals with diarrhea between the regimens.

REFERENCES

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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.

Manufacturer Information

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displayName: SPL UNCLASSIFIED SECTION
FDA Article Code: 42229-5

CLINITEST^® is a registered trademark of Miles, Inc.
CLINISTIX^® is a registered trademark of Bayer Corporation. Manufactured in Austria by Sandoz GmbH
for Sandoz Inc., Princeton, NJ 08540 This Product was Repackaged By: State of Florida DOH Central Pharmacy

104-2 Hamilton Park Drive
Tallahassee, FL 32304
United States

Label Image for 250 mg/125 mg

id: 7e0c0264-1b3a-49cc-9c55-a067f641da95
displayName: PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FDA Article Code: 51945-4